SUPPLEMENT TO JOURNAL OF PSYCHOPHARMACOLOGY

VOL 26, SUPPLEMENT TO ISSUE 8, AUGUST 2012

These papers were presented at the Summer Meeting of the

BRITISH ASSOCIATION FOR PSYCHOPHARMACOLOGY

22 – 25 July, Harrogate, UK

Indemnity

The scientific material presented at this meeting reflects the opinions of the contributing authors and speakers. The British Association for Psychopharmacology accepts no responsibility for the contents of the verbal or any published proceedings of this meeting.

BAP OFFICE 36 Cambridge Place Hills Road Cambridge CB2 1NS

bap.org.uk Aii CONTENTS

Abstract Book 2012 Abstracts begin on page:

SYMPOSIUM 1 A1 Drugs as tools in neuropsychiatry: Ketamine (S01-S04)

SYMPOSIUM 2 A2 New tricks for old drugs: Opiates, addiction and beyond (S05-S08)

SYMPOSIUM 3 A3 Advances in understanding brain corticosteroid responses to stress: relevance to depression (S09-S12)

SYMPOSIUM 4 A5 Cognitive impairment in depression: A target for treatment? (S13-S16)

SYMPOSIUM 5 A6 New treatment strategies for targeting drug addictions – A translational perspective (S17-S20)

SYMPOSIUM 6 A7 Functional imaging markers for monitoring treatment: Mechanisms and efficacy (S21-S24)

SYMPOSIUM 7 A9 Schizophrenia Treatment: What’s wrong with it and what might work better (S25-S28)

SYMPOSIUM 8 A10 Epigenetics and psychiatry - current understanding and therapeutic potential (S29-S32)

SYMPOSIUM 9 A11 Rethinking the compulsive aspects of addiction: From bench to bedside (S33-S36)

POSTERS

Anxiety 1 (MA01-MA07) A13

Affective Disorders 1 (MB01-MB20) A16

Brain Imaging (MC01-MC12) A24

Cognition 1 (MD01-MD09) A29

Educational Psychopharmacology (ME01-ME05) A33 CONTENTS Aiii

Abstract Book 2012 (continued) Abstracts begin on page:

Schizophrenia 1 (MF01-MF13) A35

Substances of Abuse 1 (MG01-MG09) A40

Anxiety 2 (TA01-TA05) A44

Affective Disorders 2 (TB01-TB21) A46

Sleep (TC01-TC05) A54

Cognition 2 (TD01-TD10) A56

Neuropharmacology (TE01-TE07) A60

Schizophrenia 2 (TF01-TF11) A63

Feeding and Eating (TG01-TG03) A67

Substances of Abuse 2 (TH01-TH15) A68

Psychomotor Stimulants (TI01-TI03) A73

POSTDOCTORAL SYMPOSIUM A74 Neurodevelopmental models of psychiatric disease: back to the future (PD01-PD04)

SHORT ORAL PRESENTATIONS

Short Orals 1: New ways to model anxiety See abstracts MA01, MA05, MA04, MA07

Short Orals 2: Cognitive enhancement: From aspiration to realisation See abstracts TD06, SO01 (page A75), TD08, TF06

Short Orals 3: Cannabinoids: Toxic effects and treatment applications See abstracts TF04, MG03, MG05, MG04

GUEST LECTURE (GL1) A75

BAP PSYCHOPHARMACOLOGY AWARD WINNERS (PW1-PW3) A76

ABSTRACTS A1

S01

THE TRANSLATIONAL NEUROPHARMACOLOGY OF KETAMINE Deakin JFW, Neuroscience and Psychiatry Dept, Univ of Manchester, G907 Stopford Building Oxford Rd Manchester M13 9PT, [email protected]

The acute psychotomimetic effects of drugs that block the ion-channel associated with the NMDA glutamate receptor such as phencyclidine and ketamine have been the focus of much research interest for several decades. More recently, therapeutic effects in depression have been reported that emerge after some hours after a single dose of ketamine. This presentation focuses on the use of ketamine to understand the mode of action of two novel drugs: minocycline for negative symptoms of schizophrenia (Chaudhry et al, J Psychopharmacol 2012 (in press)); and AZ 6765, a NMDA channel blocker for depression. The translational tools were electrophysiology and blood oxygenation level dependent (BOLD) MRI imaging of drug effects using pharmaco-MRI (phMRI). In electrophysiological studies in the rat, ketamine, like other NMDA channel-blockers, caused a marked activation of hippocampal and frontal cortical neuronal fi ring rate and desynchronisation of the predominant delta rhythm associated with α-chloralose anaesthesia. Minocycline pre-treatment completely prevented the desychronisation induced by ketamine without affecting the increased fi ring rate. Translational studies with ketamine point to a novel glutamatergic action of minocycline in facilitating integrative function in cortex. Depression has been associated with over-activity of the subgenual cingulate cortex (SCG) which normalises with recovery. An acute iv bolus infusion of ketamine was previously reported to decrease BOLD signal in SGC in healthy volunteers (Deakin JFW et al, Arch General Psychiat 2008; 65:154-64). We investigated whether AZD6765 and ketamine shared this effect in 60 depressed participants when administered as a slow intravenous infusion and whether SCG effects were associated with clinical outcome 24 and 7 days later. The study was carried out in Manchester and Oxford, UK. Against our prediction, no decreases following drug were seen in any region compared to saline. Instead both drugs gradually increased SGC BOLD signal during the infusion. SCG was the only area in which phMRI responses to drug correlated with improvement in Montgomery- Asberg mood ratings scale 24hrs and 7 days later. Interviewer-rated psychotic and dissociative symptoms were minimal and not statistically signifi cant after AZ6765 but statistically signifi cant after ketamine. Improvement in mood did not differ between active and placebo treatments. The results suggest that AZ6765 and ketamine have antidepressant - like effects on emotion processing in the brain, that these effects may be initiated by actions on the SGC, and that diminished NMDA glutamate neurotransmission is the immediate mechanism. Funding: AstraZeneca, Medical Research Council UK, Stanley Medical Research Institute

S02

KETAMINE IN HEALTHY VOLUNTEERS AS A MODEL OF SCHIZOPHRENIA Fletcher PC, Psychiatry, Univ of Cambridge, Herchel Smith Bldg Addenbrooke’s Hospital, West Forvie Site Robinson Way, Cambridge, CB2 0SZ, [email protected]

Introduction: Acute administration of the competitive NMDA antagonist, ketamine, to healthy people produces a complex array of perceptual, cognitive and motor changes that are strikingly redolent of early psychosis. The purpose of a drug model, however, should go beyond replicating key characteristics of a syndrome and should aim, in addition, to establish both construct and predictive validity. That is, it should be possible to show that the drug reproduces the key symptoms by acting on brain circuitry known to be disturbed in association with the syndrome and it should moreover be possible to show that the symptoms that it produces are related to, and predicted by, its underlying effects on brain and cognition. The work reported here explored these possibilities in the context of the ketamine model of psychotic symptoms and is based on the suggestion that these symptoms occur as a consequence of a derangement in prediction error-dependent learning. It is a model that appeals more broadly to the predictive coding model of psychosis. Methods: We used serial studies on overlapping participant groups. The aim was initially to defi ne neural markers for a specifi c prediction error-dependent learning process. Subsequently, these subjects participated in a placebo-controlled study of ketamine’s effects on perception, experience and cognitive performance. The central aim was to determine whether individual variability in neural responses to prediction error were predictive of individual vulnerability to the effects of subsequent ketamine administration. This would provide evidence of a link between a specifi c neural response, a cognitive process and a neurochemical perturbation in subjective experiences. Such a link would be valuable in assessing the validity of the cognitive model of psychosis underlying the experiment. Results: Frontal and striatal activity measured during the initial phase of testing covaried strongly with prediction error-dependent learning. Variations in these responses predicted the effects of ketamine on cognitive performance in learning tasks as well as the tendency of the drug to produce mild symptoms of psychosis. Conclusions: Administration of ketamine produces a constellation of perceptual and cognitive effects, as well as psychosis-like symptoms. As well as being strikingly redolent of early psychotic illness, these are related to alterations in prediction error-dependent learning processes. People in whom neural responses to such processes are greater appear to show increased vulnerability to the drug’s effects. This intimate relationship between process-specifi c neural responding and ketamine-related disturbance may offer important insights to the neurobiology of how psychotic symptoms emerge.

S03

KETAMINE AND THE POTENTIAL ROLE FOR RAPID ACTING ANTIDEPRESSANTS Krystal JH, Psychiatry Yale University School of Medicine, 300 George St., Suite 901, New Haven, CT 06511 USA [email protected]

There is a tremendous need for antidepressant treatments that work more rapidly and more effectively than available treatments. Our current antidepressant treatments (monoamine reuptake or metabolism modulators, lithium, ECT) have been in place for over 50 years. This presentation will review the path that let to the identifi cation of ketamine as the fi rst rapid onset antidepressant treatment. Ketamine is a short-acting NMDA glutamate receptor antagonist. A series of studies now demonstrate that a single intravenous dose of ketamine will produce reductions in depression severity within several hours and remission of depression in many patients within 24 hours. The antidepressant effects of a single dose of ketamine appear to last generally, from several days to several weeks. In light of evidence that suicidal ideation improves with other symptoms of depression, the potential role of ketamine and other rapid acting antidepressants will be considered briefl y. Building on molecular insights into the mechanisms through which ketamine appears to produce its antidepressant effects, novel alternatives to ketamine will be discussed. 1: Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-4. 2: Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-64. 3. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-64. 4. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475(7354):91-5. 5. Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7(5):426-37. Acknowledge support from National Institute on Alcohol Abuse and Alcoholism, 2P50 AA 012870, National Center Post Traumatic Stress Disorder, Clinical Neurosciences Division, West Haven, CT, for their support A2 ABSTRACTS

S04

ANIMAL MODELS OF NEUROPSYCHIATRIC DISORDERS: KETAMINE AND RELATED DRUGS Steckler T, Neuroscience Drug Discovery, Janssen R&D, Turnhoutseweg 30, Beerse, Belgium, 2340 [email protected]

N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive NMDA antagonists is amongst the most frequently used manipulations to model schizophrenia in animals, including acute, subchronic and neonatal administration of phencyclidine (PCP), MK-801, memantine and ketamine. In particular ketamine received much attention due to its potential translational value, allowing comparison between its effects in animals and studies in healthy volunteers behaviourally but also with electrophysiological and imaging techniques. Despite the translational value of ketamine, it is evident that the most popular NMDA antagonist used in animal models of schizophrenia is PCP, which in general produces more robust effects in rodents. For example, we observed accuracy defi cits in a touch-screen paired associate task in rats induced by PCP, while ketamine, even at higher dose range, only affected responsivity, but not accuracy. In part this may be related to different pharmacokinetic properties of the drugs, although it is evident that different NMDA antagonists also exert qualitatively different effects. Furthermore, it is evident that subchronic and neonatal administration of NMDA antagonists resembles the neuroanatomical and neurochemical changes observed in schizophrenic patients more closely and that those models can be of utility as preclinical tests for effi cacy of compounds, yet those models lack translatability to healthy volunteers. Thus, while ketamine and related drugs may be considered to be of interest from a translational perspective, there are important gaps that are diffi cult to bridge. These translational challenges, as well as the utility of these antagonist models for drug discovery will be discussed.

S05

ENHANCING THE PHARMACOLOGY OF BUPRENORPHINE AS A TREATMENT FOR DRUG ADDICTION Bailey CP, Dept of Pharmacy and Pharmacology, Univ of Bath, Claverton Down, Bath BA2 7AY [email protected]

The opioid drug, buprenorphine, has been in clinical use since the 1970s, initially as an analgesic, but increasingly as a treatment for drug addiction in the form of substitution therapy for opiate addicts. Its use as opiate substitution therapy derives from its well-characterised action as a low-effi cacy mu-opioid receptor (MOPr) agonist, with slow dissociation rate. Thus, there is a relatively low risk of overdose, its effects are long-lasting, and occupancy of buprenorphine at MOPr is not readily displaced by on-top use of other MOPr agonists such as heroin/morphine. However, we have gradually realised that buprenorphine has other pharmacological actions that may in fact enhance its utility as a therapy not only for opiate addiction but for addiction to other drugs of abuse. Firstly, buprenorphine is a kappa-opioid receptor (KOPr) antagonist, with roughly equivalent affi nity at KOPr as at MOPr. There is extensive recent preclinical evidence that KOPr antagonists may be effective at inhibiting drug-seeking behaviour for a range of drugs of abuse including opiates, psychostimulants and ethanol. Furthermore, it has been reported that buprenorphine is a low-effi cacy agonist at the nociceptin/orphanin FQ receptor (NOPr). Again, several studies have shown the involvement of NOPrs in the rewarding and reinforcing properties of opiates, psychostimulants and ethanol. Thus, the polypharmacology of buprenorphine may cause it to be an effective treatment for poly-drug abuse. In order to enhance and optimise the pharmacological features of buprenorphine, it would be desirable to minimise effi cacy at MOPr while retaining affi nity, to enhance affi nity at KOPr, and to enhance potency at NOPr. The resulting mixed very-low-effi cacy MOPr agonist / KOPr antagonist / NOPr agonist might be expected to be a non-rewarding/ non-aversive treatment for poly-drug addiction. Two approaches designed to achieve this aim are: the design and development of novel single compounds that have this polypharmacology, and, delivery of buprenorphine in combination with an opioid antagonist such as naltrexone.

S06

OPIOID ANTAGONISTS FOR ALCOHOL DEPENDENCE Mann K, Central Institute of Mental Health Mannheim, Univ of Heidelberg, Heidelberg, Germany [email protected]

Studies with naltrexone and nalmefene will be covered. The PREDICT study (N=426, Mann et al 2009) showed no benefi t of naltrexone (and acamprosate) over placebo. However, with the use of fMRI, genotyping and psychometrics, subgroups of patients could be formed and potential naltrexone responders were identifi ed. The main focus of the presentation will be on three unpublished multi-centre, double-blind, placebo-controlled phase III studies, designed to assess the effi cacy and safety of nalmefene in reducing alcohol consumption. Despite a long period (>10 years) of problem drinking, the vast majority of the alcohol dependent patients included in the nalmefene clinical trials had not previously received any treatment for their condition, underlining the need for a new approach to treating these patients. In the two effi cacy studies, nalmefene was superior to placebo in reducing the number of heavy drinking days (HDDs) and total alcohol consumption (TAC) at Month 6. In the 1-year safety study, nalmefene was superior to placebo in reducing the number of HDDs and TAC at the majority of the time points and at the end of the study. In all the studies, the effect of nalmefene was evident already at month one and was maintained throughout the treatment period. For all three studies, improvements in CGI scores and reductions in liver enzymes amma-glutamyltransferase and alanine aminotransferase from baseline were larger in the nalmefene group compared to placebo throughout the study periods. The most frequent adverse events reported included dizziness, insomnia and nausea, and were mild and transient. The majority of these events had an onset within the fi rst days after the fi rst dose and decreased with treatment continuation. In conclusion, a personalised medicine approach with naltrexone seems promising. Nalmefene could be used to reduce alcohol consumption in alcohol dependent patients and thus strengthen the individual attempts to regain behavioural self-control over drinking. Studies with naltrexone and nalmefene will be covered. The PREDICT study (N=426, Mann et al 2009) showed no benefi t of naltrexone (and acamprosate) over placebo. However, with the use of fMRI, genotyping and psychometrics, subgroups of patients could be formed and potential naltrexone responders were identifi ed. The main focus of the presentation will be on three unpublished multi-centre, double-blind, placebo-controlled phase III studies, designed to assess the effi cacy and safety of nalmefene in reducing alcohol consumption. Despite a long period (>10 years) of problem drinking, the vast majority of the alcohol dependent patients included in the nalmefene clinical trials had not previously received any treatment for their condition, underlining the need for a new approach to treating these patients. In the two effi cacy studies, nalmefene was superior to placebo in reducing the number of heavy drinking days (HDDs) and total alcohol consumption (TAC) at Month 6. In the 1-year safety study, nalmefene was superior to placebo in reducing the number of HDDs and TAC at the majority of the time points and at the end of the study. In all the studies, the effect of nalmefene was evident already at month one and was maintained throughout the treatment period. For all three studies, improvements in CGI scores and reductions in liver enzymes amma-glutamyltransferase and alanine aminotransferase from baseline were larger in the nalmefene group compared to placebo throughout the study periods. The most frequent adverse events reported included dizziness, insomnia and nausea, and were mild and transient. The majority of these events had an onset within the fi rst days after the fi rst dose and decreased with treatment continuation. In conclusion, a personalised medicine approach with naltrexone seems promising. Nalmefene could be used to reduce alcohol consumption in alcohol dependent patients and thus strengthen the individual attempts to regain behavioural self-control over drinking. ABSTRACTS A3

S07

ROLE OF KAPPA OPIOID RECEPTORS IN STRESS AND DEPRESSION Bailey SJ, Pharmacy and Pharmacology, Univ of Bath, Claverton Down, Bath BA2 7AY [email protected]

Until the 1950s, opiates were used to treat depression. With the development of monoamine oxidase inhibitors and tricyclic antidepressants, opiates fell out of favour because of their abuse and physical dependence liability. Over the last decade, interest has grown in kappa opioid receptors as potential targets for treating a range of psychiatric disorders, including mood disorders (Bruchas et al., 2010. Brain Res 1314: 44-55; Knoll et al., 2010 Brain Research 1314: 56-73). The endogenous opioid peptides dynorphins are released and activatekappa receptors during exposure to acute or subchronic stress. Kappa-agonists induce dysphoric responses in humans and aversive responses in rodents; whereas kappa-antagonists, kappa-receptor gene deletion or prodynorphin gene disruption have antidepressant-like effects in the forced swim test. Concern about the feasibility of developing kappa-antagonists for therapeutics has centred on an unusual pharmacodynamic property of prototypic kappa-selective antagonists. In animal models, a single injection of, for example, the kappa-antagonist norbinaltorphimine produces peak effects occurring ~24h post- administration, with maximal levels maintained for 7-10 days, returning to control levels over 3-4 weeks. Such a pharmacodynamic profi le, limits in vivo behavioural testing and, potentially, clinical trials if the blockade of kappa-receptors cannot be readily reversed. Recent work by ourselves and others towards developing short-acting kappa-antagonists, with both anxiolytic and antidepressant activity in mice, will be discussed.

S08

RISK OF DEATH DURING AND AFTER OPIATE SUBSTITUTION THERAPY: EVIDENCE FROM EUROPEAN AND AUSTRALIAN COHORTS Hickman M, School of Social and Community Med, Univ of Bristol, Canynge Hall, Whatley Road, Bristol BS8 2PS [email protected] Louisa Degenhardt, UNSW Sydney; Marina Davoli, Lazio; Fabrizio Faggiano, Turin; John Strang, IOP London; Roy Robertson, Edinburgh; John Macleod, Bristol; Jo Kimber, UNSW Sydney.

Introduction: We know that: drug related mortality risk is high among opioid and injecting drug users; the risk of mortality is reduced during specialist drug treatments (especially opiate substitution treatment (OST); but there are temporary increases in mortality risk both at treatment initiation and cessation. Methods: Mortality Cohorts Results: In Western Europe and Australia, opiate users’ mortality risk can be 1-2% annually: >10 times higher than the general population. Death rates during OST are 2 to 5-fold lower than the mortality risk out of treatment. In Italy and the UK, the overdose and all-cause mortality rates were 8-10 fold higher in the month following treatment, compared to the mortality rates after the fi rst month of treatment. There was no evidence of a marked difference in the mortality rates after treatment in those prescribed methadone or buprenorphine, but some suggestion that overdose deaths in the fi rst two weeks may be lower in those initiated on buprenorphine rather than methadone. Conclusions: Natural history studies in UK illustrate the persistence of addiction and high probability of relapse following periods of abstinence, as well as improved survival in patients exposed to prolonged drug treatment. These fi ndings raise several important issues for clinicians and policy-makers. First, increasing treatment duration as well as scaling-up treatment delivery may be critical to achieving a reduction in drug related deaths in the population. In the UK a fi ve-fold scale- up of OST, though associated with a reduction in methadone related deaths per daily dose after the introduction of supervised consumption, did not lead to any observed reduction in the overall number of opiate related deaths. Second, the few cohorts available suggest that the risk of mortality during and after treatment can vary. E.G. the risk of overdose during treatment was lower in Italy than Australia or UK. Therefore, it is critical that large-scale cohort studies are conducted in other countries, especially before scaling up treatment, to assess these potential variations, and determine minimum durations of treatment to effect reductions in drug-related deaths in the population. References:M. Davoli et al., Addiction 102, 1954 (2007); R. Cornish, J. Macleod, J. Strang, P. Vickerman, M. Hickman, BMJ 341, c5475 (2010); L. Degenhardt et al., Drug Alcohol Depend. 105, 9 (2009); L. Degenhardt et al., Addiction 106, 32 (2010); J. Kimber et al., BMJ 340, c3172 doi:10.1136/bmj.c3172 (2010) .

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ULTRADIAN PATTERNS OF CORTICOSTERONE RELEASE AND THEIR INFLUENCE ON HEALTHY STRESS RESPONSES: A TRANSLATIONAL APPROACH Lightman SL, Henry Wellcome Labs for Integrative Neuroscience and Endocrinology, Univ of Bristol, Dorothy Hodgkin Bldg, Whitson Street, Bristol BS1 3NY [email protected]

Hormones that are regulated through a rapid feedforward:feedback mechanism must show oscillations in plasma levels [Walker et al 2010, Proc Biol Sci; 277(1688):1627- 33]. Cortisol (in man) and corticosterone (in the rodent) are no exception. We have been able to demonstrate that the oscillations in cort are regulated at sub-hypothalamic level through the interaction between feedforward of ACTH on cort secretion and the feedback of cort on ACTH section [Walker et al 2012, PLoS Biology - in press]. Changes in hypothalamic drive result in changes in the size of cort pulses, but not in their frequency. Furthermore, the physiological circadian regulation of pulsatility appears to result from a withdrawal of SCN mediated inhibition during the active phase (night-time in the rodent), since abolition of circadian rhythmicity by SCN lesions results in pulsatility extending beyond the normal nocturnal periods through the full 24 hours. Oscillations of total cort in the plasma are mirrored by oscillations of free cort in the brain [Droste et al 2008, Endocrinology; 149(7):3244-3253], so the question arises as to the biological signifi cance of this pattern of cort presentation to GR and MR. Pulsatility of cort results in gene pulsing both in vitro and in vivo [Stavreva et al 2009, Nature Cell Biology; 11:1093-1102], and there are signifi cant differences in gene response to constant or pulsatile cort administration. Interestingly, we have been able to show in the whole animal that pulses of cort are associated with waves of binding of GR (but not MR) and the histone acetyltransferase complex CBP/p300 with transient localised changes in lysine acetylation at GC regulatory regions and concomitant recruitment of RNA polymerase II [Conway-Campbell et al 2011, Molecular Endocrinology;25(6):944-54]. The pattern of glucocorticoid secretion is important for localised CNS responses, as well as neuroendocrine and behavioural responses to stress. Constant levels of cort result in a blunted ACTH response to a stressor [Sarabdjitsingh et al 2010, Endocrinology; 151(11):5369-79]. Furthermore, there are pulse phase dependent effects in both ACTH and behavioural responses to a stressor, as well as differential c-fos activation in the PVN, amygdala and hippocampus. These responses are both pulse phase and pulse amplitude dependent suggesting different stress circuits are differentially responsive to the pattern of glucocorticoid exposure. The oscillatory pattern of cort appears to be critical for normal physiological responses to a stressor and may also play a role in modulating emotional response. Financial sponsorship: MRC, BBSRC, Wellcome Trust A4 ABSTRACTS

S10

RAPID AND SLOW EFFECTS OF CORTICOSTEROIDS IN THE RODENT AND HUMAN BRAIN: RELEVANCE FOR COGNITIVE PERFORMANCE Joels M, Dept. Neuroscience and Pharmacology UMC Utrecht, Stratenum, Universiteitsweg 100 Utrecht, The Netherlands 3584 CG, [email protected]

The brain is exposed to high levels of corticosteroid hormones (corticosterone in rodents; cortisol in humans) shortly after stress; hormone levels are normalized within 2 hrs. In the brain these hormones bind to two types of receptors: mineralocorticoid and glucocorticoid receptors (MR and GR) which are enriched e.g. in the hippocampus, parts of the prefrontal cortex and amygdala nuclei. Up till recently, corticosteroid receptors were thought to act only via transcriptional regulation of responsive genes, thus changing neuronal activity in a slow but persistent manner. Most of these stress-induced actions involve the GR. More recently it has become evident that corticosteroids also change neuronal function more rapidly, within minutes after stress. This can occur via MR or GR. We examined the rapid and slow actions of corticosteroids --either given exogenously or being released in response to stress—on neuronal function and behavioral performance in rodents as well as healthy human volunteers. The slow, genomic effects of corticosteroids are most consistent. They promote higher cognitive functions, such as the consolidation of contextual aspects of fearful conditions (so that this information is not generalized across different contexts), working memory performance with a moderate cognitive load and (economic) decision making with a long-term perspective. In humans, this phase is linked to increased dorsolateral prefrontal activity. In the rodent brain, facilitated glutamatergic transmission in the hippocampus and prefrontal cortex has been reported, while general transfer of electrical activity in the hippocampus is attenuated and synaptic strengthening (unrelated to the stressor) at that time is strongly impaired. Rapid corticosteroid effects are more diffi cult to target in the human brain, due to the peripheral administration of cortisol. Most studies tend to show more present-bias in decision making, impaired working memory performance and emotional interference linked to a tendency for reduced prefrontal function. At the single cell or circuit level, rapid actions are characterized by greatly enhanced background glutamatergic activity, mediated by MRs; this has been observed both in the dorsal hippocampus and basolateral amygdala. By precisely timing cortisol administration relative to the task that has to be performed, specifi c systems may be targeted. The current data support the notion that particularly in the delayed domain, cortisol administration may promote higher cognition control. This may be of relevance for the treatment of psychiatric disorders where these higher cognitive functions are disturbed.

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ARE CORTICOSTEROIDS ESSENTIAL FOR ANTIDEPRESSANT RESPONSE? EVIDENCE FROM PRECLINICAL STUDIES Herbert J, Clinical Neurosciences, Univ of Cambridge, Brain Repair, Centre Forvie Site, Cambridge CB20PY [email protected]

Depression (MDD) is characterised by multiple disturbances in the hypothalamo-pituitary-adrenal (HPA) axis, including disturbed diurnal rhythms, increased resistance to negative feedback and accentuated post-awakening surges. In addition, prolonged excess cortisol or corticoids, whether endogenous, pathological or therapeutic, represent a risk for MDD. Experimental studies of MDD are hampered by poor animal ‘models’, but there is increasing interest in the role of hippocampal neurogenesis in MDD, and the way this is moderated by corticoids, though parallels with MDD must be assessed with caution. There is experimental evidence that the effi cacy of SSRIs is compromised by a fl attened daily corticoid rhythm. Cortisol also helps to organise the circadian system, so disturbances in daily cortisol rhythms can have complex results on dependent corticoid dependent or independent gene expression; these can alter affective state. Whether restitution of these rhythms might aid response to treatment is still unknown. Higher levels of cortisol increase the risk for MDD, but the relative contribution of mineralocorticoid or glucocorticoid receptors, or membrane-bound actions, is uncertain. Cortisol, its rhythms and the response to stress are altered by early adversity, and by puberty (particularly in females); these may represent mechanisms of risk. Corticotrophin-releasing factor (CRF), a central component of the HPA, may also contribute to symptoms of MDD, most likely anxiety. Corticoids have powerful actions on BDNF, and thus on neural plasticity, which has been implicated in MDD or its recovery, and on the immune system. Cytokines can induce experimental ‘sickness’ behaviour, a plausible feature of MDD, and reduce neurogenesis. They also induce MDD in humans. Both cytokines and corticoids can reduce serotonin, but promote the formation of the neurotoxin quinolinic acid (via the kynurenine pathway), which may be involved in MDD. DHEA, which moderates the actions of cortisol, and stimulates neurogenesis, might well play an adjunctive role in MDD treatment, particularly in older patients. Overall, it is time that clinical psychiatry took a deeper interest in the contribution of disturbances in the HPA axis to the risk for MDD, refi ning its nosological complexity, variations in its course, and to the relative ineffectiveness of current treatments

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UPSTREAM: GENETIC POLYMORPHISMS REGULATING GLUCOCORTICOID-STIMULATED GENE EXPRESSION – RELEVANCE FOR THE PATHOPHYSIOLOGY AND TREATMENT OF DEPRESSION Binder EB, RG molecular genetics of depression, Max-Planck Institute of Psychiatry, Kraepelinstr. 2-10 Munich Germany 80804 [email protected]

Exposure to stressful life events is one of the strongest established risk factors for the development of major depression. The stress hormone axis is one of the systems orchestrating the short and longterm effects of stress on the organism and a dysregulation of this system has been implicated in the pathophysiology of major depression. One of the main effectors of this system is the glucocorticoid receptor (GR), a nuclear receptor with transcription factor function. Genetic polymorphisms that alter the transcriptional effects of GR-activation might alter the short term as well as longterm effects of exposure to stress and thus the risk to suffer from major depression. Data from genome-wide gene expression before and after stimulation of the GR with 1.5 mg of dexamethasone in peripheral blood of 160 male individuals will be presented and combined with genome-wide SNP data for expression (eQTL) and DNA methylation quantitative trait locus (mQTL) analysis on GR-stimulated gene expression. Over 2,300 signifi cant response eQTLs, i.e., loci that are only associated with variation in GR-stimulated gene expression changes, but not with baseline gene expression were identifi ed. These response eQTLs show a longer average SNP/probe distance of 406 kb than baseline eQLTs (136 kb) indicating a more long range regulation of gene expression by the GR. We not only observed an enrichment of GR response elements in response eQTL SNP sequences but also transcription factor (TF) binding sites that have been previously shown to be important for GR transcriptional effects, including AP1, HNF4 and OCT1. The response eQTL SNPs were enriched in loci previously been reported to be associated with depression. Interestingly, the majority of these overlapping SNPs does not alter the gene expression of the closest gene but of more distant genes. For example, SNPs within the CLOCK gene moderate the gene expression of PAICS, which is 947 kb upstream of the CLOCK gene. The same SNP set was also enriched among SNPs associated at p <= 0.05 with major depression in the mega-analysis of the Psychiatric Genomics Consortium, both compared to random as well as baseline eQTL SNPs (p < 0.001). In summary, using functional annotation of SNPs that may refl ect differences in reactivity to stress, such as GR-stimulated gene expression appears to be a promising tool for a better understanding of the genetic risk factors of major depression and identify new target for antidepressant treatment strategies. This study has been funded by an ERC starting grant and the Max-Planck Society. ABSTRACTS A5

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COGNITIVE DEFICITS IN MOOD DISORDERS: AN UPDATE ON IMAGING AND BEHAVIOURAL FINDINGS Roiser JP, Inst of Cognitive Neuroscience, University College London, 17 Queen Square, London WC1N 3AR [email protected]

Depression is a debilitating psychiatric disorder associated with heavy economic and social costs. Although traditionally considered not to entail substantial cognitive defi cits (unlike, say, schizophrenia), in fact depressed individuals reliably score lower than matched healthy volunteers on standard neuropsychological tests. This talk will present an overview of “hot” (involving affective processing) and “cold” (not involving affective processing) cognitive abnormalities in depression, demonstrating that the latter are surprisingly consistent, and even present in remitted subjects, suggesting the possibility that they may represent trait markers. Results from a recent systematic meta-analysis based on data from the Cambridge Neuropsychological Test Automated Battery (CANTAB) will be presented, on which effect sizes (Cohen’s d) of between ~0 (choice reaction time) and ~0.9 (selective attention) were identifi ed across around 20 case-control studies of unipolar depression (Rock et al, in preparation). Surprisingly, the analysis of subjects with bipolar disorder, including around half as many studies, produced similar results. Preliminary data from remitted depressed subjects suggested continuing impairment on some, but not all domains following recovery. In the second half of the talk, neuroimaging fi ndings relevant to cognitive impairment will be presented. Specifi cally, it will be suggested that despite relatively spared working memory performance, subjects with depression exhibit increased dorsal prefrontal cortex responses with increasing task diffi culty, relative to healthy volunteers. Importantly, cognitive impairment and associated abnormally high dorsal prefrontal responses predict poor outcome following antidepressant treatment. However, unlike the effects of antidepressants on abnormal neural responses to “hot” stimuli, longitudinal studies do not suggest that standard treatments for depression resolve such “cold” cognitive and neural abnormalities. Therefore it is possible that treatment-resistant depressed patients may benefi t from add-on interventions targeted at cognitive impairment. Three examples of possible interventions will be examined: modafi nil; direct current magnetic stimulation; and cognitive training. While small, preliminary, laboratory studies suggest that each approach holds promise for improving outcome in treatment-resistant depression via boosting cognition, it remains to be seen whether such strategies will prove effi cacious in larger clinical trials. The meta-analysis presented was supported by Cambridge Cognition Ltd.

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RODENT MODELS OF EMOTIONAL DYSFUNCTION: POTENTIAL TARGETS FOR TREATMENT Robinson ESJ, School of Physiology and Pharmacology, Univ of Bristol, Medical Sciences Bldg, University Walk Bristol BS8 1TD [email protected]

Recent developments in clinical research suggest that negative biases in cognition and emotional processing have a central role in mood disorders. It is also hypothesised that these cognitive processes are a key site of action for antidepressant drugs. Studying these processes in non-human species offers a means to understand them and develop new treatments to address issues such as effi cacy and rate of onset of action. Established models of depression, such as the forced swim test, have good predictive validity but limited translational validity, particularly when considering the cognitive impairments and emotional dysfunction. Using ‘reverse translation’, a number of new rodent models of cognitive affective behaviour have been developed. The fi rst example of cognitive affective bias in rodents was described by Harding et al., 2004 (Nature 427, 312) who showed that induction of a negative affective state resulted in reduced anticipation of positive outcomes in response to ambiguous cues, suggesting a negative judgement bias. Since this landmark paper, similar observations have been made in a number of species from man (Anderson et al., 2012; CABN, in press) to bees (Bateson et al., 2011, Curr. Biol. 21, 1070-3). As well as effects on judgment, affective states have been shown to bias memory particularly in relation to the recall of emotional information. Studies in man have mainly focused on memory for emotional information; however, we hypothesised that similar effects may infl uence other types of information processing including memory for rewarding experience. We developed a task where we could assess the impact of affective state on reward learning and, in particular the relative value attributed to rewarding experiences encountered under different affective states. We have found that a reinforcer’s appetitive value is directly modifi ed when learnt during different affective states. We provide evidence that this task is sensitivity to both anti-depressant and pro-depressant effects induced by pharmacological or psychosocial manipulations. The effects we observe are not dependent on a congruent affective state at recall and suggest a specifi c mechanism involving memory consolidation. In summary, these examples illustrate important new approaches for studying emotional dysfunction in animals. They provide a signifi cant advance in terms of non-clinical methods to study cognitive mechanisms in mood disorders with improved predictive and translational validity. This work was funded by an RCUK academic fellowship awarded to ESJR with additional fi nancial support provided by the British Pharmacological Society Integrative Pharmacology Fund and a BBSRC Industrial CASE studentship with Pfi zer, UK

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PRIMATE MODELS OF COGNITIVE DYSFUNCTION IN DEPRESSION: MONOAMINERGIC MODULATION OF EMOTIONAL BEHAVIOUR AND EXECUTIVE FUNCTION Clarke HF, Dept of Physiology, Development and Neuroscience, Univ of Cambridge, Downing Street, Cambridge CB2 3DY [email protected]

Depression is a prevalent psychiatric disorder characterised by low mood, anhedonia and abnormalities in the cognitive processing of affective information. Animal studies and extensive neuroimaging evidence from humans suggest that the same structures found to function abnormally in depression - the orbitofrontal and medial prefrontal cortices, striatum, amygdala and hippocampus - are also important for processing appetitive and aversive reinforcement. Consistent with the effi cacy of monoaminergic medication in the treatment of depression, these areas are also strongly innervated by both serotonin and dopamine, and patients and healthy populations show differences in the responsivity of these regions to monoaminergic drug challenges on tasks involving affective processing. These fi ndings have led to the hypothesis that abnormalities in these regions, possibly driven by alterations in monoaminergic function, lead to maladaptive reinforcement processing. Such changes result in diffi culty altering behaviour appropriately in response to positive or negative feedback, and a subsequent predisposition to a depressive state. Although appealing, this proposal is hampered by a lack of understanding into the precise anatomical roles of the monoamines in reinforcement processing, and the limitations of the experimental interventions possible in humans. However, the close functional and anatomical similarity between human and monkey brains, compared to rodents, makes the monkey an ideal model for probing the roles of specifi c monoamines in affectively driven behavioural tasks similar to those used in humans, with a high degree of anatomical accuracy. This talk will therefore review work investigating the effects of both excitotoxic lesions and neurochemically specifi c depletions in the orbitofrontal cortex, striatum and amygdala of rhesus and marmoset monkeys on tasks involving reward and punishment processing, such as probabilistic and non-probabilistic reversal learning. Evidence that serotonin and dopamine manipulations can differentially affect both reward and punishment processing will be presented, and discussed with respect to human fi ndings of more specifi c serotonergic effects on reward. Individual monoamines do not fulfi l the same roles within different nodes of a fronto-striatal loop, highlighting the importance of understanding the anatomical specifi city of behavioural effects when considering medications that act globally. Finally, future investigations into subgenual prefrontal cortex and hippocampus will be considered. Supported by a Wellcome Trust Prize Studentship (HFC); the JS McDonnell Foundation; a Wellcome Trust programme grant (to TW Robbins, BJ Everitt, AC Roberts, BJ Sahakian); The Newton Trust, Cambridge; and Newnham College, Cambridge. HFC is currently supported by an MRC Career Development Fellowship. Research conducted within the University of Cambridge Behavioural and Clinical Neuroscience Institute, supported by the MRC and the Wellcome Trust. A6 ABSTRACTS

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PHARMACOLOGICAL TREATMENT OF COGNITIVE IMPAIRMENT IN MOOD DISORDERS: SOMETHING OLD, SOMETHING NEW, SOMETHING BORROWED BUT EVERYTHING BLUE Bhagwagar Z, GCR and Dept of Psychiatry, Bristol-Myers Squibb, 5 Research Parkway Wallingford CT USA 06492, [email protected]

Cognitive dysfunction in mood disorders especially major depressive disorder is increasingly being recognized as a signifi cant concern though the specifi c nature and etiology are still unclear. While this issue is much less well understood as compared with cognitive dysfunction associated with schizophrenia there are some parallels. Subtle defi cits cognitive function can be elicited in patients during an acute depressive or manic episode and some of these defi cits persist after resolution of symptoms of depression and into euthymia. The nature of these defi cits can broadly be categorized as those relevant to traditional neuropsychological paradigms or those that result in subtle defi cits in emotional processing. The neurobiological substrates of cognitive dysfunction in mood disorders remain to be elucidated. While some targets have been identifi ed for cognitive dysfunction associated with schizophrenia it is unclear if they represent viable targets for the treatment of mood disorders. It is unclear if pathways/targets implicated in the etiopathogenesis of mood disorders are specifi cally responsible for the cognitive dysfunction seen in mood disorders. If not, the identifi cation and remediation of specifi c biological targets for the treatment of cognitive impairment in mood disorders remains to be understood and may be a bridge too far. Notwithstanding this backdrop, there have been recent small steps in the treatment of cognitive impairment in mood disorders with emerging and encouraging results. The targets studied represent a mix of traditional approaches with a mix of some novel targets and the results have been mixed. Despite some success, a number of major issues still remain unresolved including the issue of pseudospecifi c effect of remediation of cognitive function with the depressive syndrome in mood states, specifi c targets and an unclear regulatory backdrop. While we are at the threshold of potentially signifi cant advances in each of these areas a lot of work needs to be done before cognitive dysfunction in mood disorders can be effective addressed with pharmacological treatments. Acknowledgments: Zubin Bhagwagar is a full time employee at Bristol-Myers Squibb and has an adjunct appointment at the Department of Psychiatry, Yale University

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ANIMAL MODELS OF NICOTINE DEPENDENCE BASED ON ASSOCIATIVE LEARNING TO TARGET CUE REACTIVITY Shoaib M, Psychobiology Labs, Inst of Neuroscience, Medical School, Newcastle Univ, Framlington Place, Newcastle NE2 4HH [email protected]

Discrete cues, such as drug-associated paraphernalia, play an important role in tobacco smoking and relapse. While an extensive human clinical literature exists, the research is limited in its ability to study mechanisms and underlying neuropharmacology. Fortunately, such effects can be modeled in the nicotine-seeking behaviour of laboratory animals. These animal models of cue reactivity show that both discrete cues and larger environmental contexts associated with previous self-administration can trigger reinstatement after extinction, which has been taken as a model for human relapse. However, these paradigms are imperfect as models of human relapse, both structurally (e.g., the contingencies for self-administration) and in terms of fi ndings. In particular, while some compounds that are clinically effective for smoking cessation can attenuate reinstatement of nicotine-seeking behaviour (e.g. rimonabant & varenicline), the mechanisms behind these actions are still unknown, and the parallels to human cue reactivity have not been fully understood. There is also a need for better measures of cue reactivity that incorporate physiological endpoints that may predict cue reactivity and relapse. Nevertheless, these animal models of relapse have the potential for identifying and screening smoking cessation medications. Research supported by internal funds from Newcastle University

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ENVIRONMENTAL DETERMINANTS OF ADDICTION-RELATED BEHAVIOURS IN RODENTS: FOCUS ON ENVIRONMENTAL ENRICHMENT Solinas M, INSERM U-1084, Experimental and Clinical Neurosciences Lab, Univ of Poitiers, 1 Rue George Bonnet, Poitiers-FRANCE, 86022 marcello.solinas@ univ-poitiers.fr

Whereas a genetic predisposition may exist, accumulating evidence demonstrates that life experiences and environmental conditions play a major role in determining whether or not psychiatric diseases are developed, their severity and the ability of individuals to recover from them. For example, negative environmental factors exacerbate addiction to drugs of abuse such as amphetamine, cocaine, and heroin. On the other hand, others and we have demonstrated that exposure to positive environmental conditions such as environmental enrichment (EE), reduces the development of addiction-related behaviors and reduces the risks of relapse in animals that are already “addicted”. Among the many and complex effects of EE on the brain and behavior, anti-stress effects appear to play a pivotal role in the ability of EE to reduce the risks of addiction. Thus, on the one hand, the antistress effects of EE would reduce the reinforcing effects of drugs and their ability to induce long-lasting neuroplastic changes that are associated with the development of drug addiction. On the other hand, restoration of the normal functioning of the stress system would render animals less sensitive to stimuli associated with drug use and consequently decrease the risks of relapse. These results suggest that environmental conditions that are challenging and stimulating, but provided in non-hostile context, greatly decrease vulnerability to addiction. Here we present this theoretical framework and recent evidence that helps characterizing and determining the boundaries of positive effects of EE on drug addiction. ABSTRACTS A7

S19

THE ROLE OF CONTEXTS IN PROMOTING AND PREVENTING RELAPSE TO DRUG SEEKING McNally GP, School of Psychology The University of New South Wales Sydney, NSW, Australia 2052 [email protected]

In animal models and human drug users, contexts play an important role in promoting as well as preventing relapse to drug seeking. Preclinical studies of extinction and reinstatement in rodents have identifi ed the neural circuits which enable contexts to contribute to and protect from relapse. These dual roles are associated with corticostriatal, amygdalostriatal, and corticohypothalamic circuits converging on distinct regions and neuronal populations in the hypothalamus, where orexingenic and anorexigenic peptides promote and prevent relapse to drug seeking. The actions of lateral hypothalamic orexin neurons, projecting to the ventral tegmental area, are important for promoting drug seeking whereas the actions of medial hypothalamic dynorphin neurons projecting to midline and intralaminar thalamus are important for preventing drug seeking. These circuits mediate abstinence from drug seeking caused by extinction training in animal models, contribute to the deepened extinction of drug seeking observed in protocols designed to disrupt the ‘reconsolidation’ of drug cue memories, and contain several targets for pharmacological intervention. Supported by grants from the National Health and Medical Research Council and Australian Research Council

S20

THE ROLE OF ATTENTION AND THE IMPACT OF SUBSTANCE CUES IN MEDIATING GOAL-DIRECTED SUBSTANCE-SEEKING Rose AK, Experimental Psychology, Univ of Liverpool, 2.32 Eleanor Rathbone Bldg, Bedford St South, Liverpool L69 7ZA [email protected] Hogarth L(1), Brown K(2) (1) Univ of New South Wales, Sydney, NSW 2052, Australia (2) Univ of Liverpool, Liverpool, L69 7ZA UK

Devaluation techniques help to identify the role of goal-directed and habit-like learning in substance-seeking behaviour. Animal research suggests that substance-seeking becomes impervious to devaluation and that presentation of substance cues can trigger substance-seeking irrespective of the substance’s current value. Within human research, hazardous substance users demonstrate attentional biases for substance cues, a process which may be important in initiating and maintaining substance-related behaviour. Together, fi ndings suggest that substance-seeking is initially an intentional choice, but becomes more habit-like and under more direct control by substance- related stimuli (which attract excessive attention). This transition may play a role in the perseveration of substance use under rising costs, bingeing, and relapse. Research investigated 1) the impact of devaluation on self-reported substance urge; 2) the impact of alcohol cues on nicotine-seeking behaviour following nicotine devaluation, during extinction (no response outcome feedback) and reacquisition (with response outcome feedback) choice trials; 3) the impact of alcohol devaluation on alcohol- seeking behaviour while directly measuring attention (eye-tracking) to alcohol cues. In the alcohol/nicotine study, nicotine was devalued by smoking to satiety. Half of the participants completed post-devaluation choice tasks in the presence of alcohol (alcohol expectancy), while the other half completed the tasks in the presence of water (non-alcohol expectancy). There was an overall decrease in smoking urge following satiety devaluation [F(1,69) = 20.62, p<.001]. Alcohol expectancies knocked out the nicotine devaluation effect which was observed during extinction choice trials in the non-alcohol expectancy condition [F=4.54, p<.05], there was no effect of devaluation during requisition trials. In the alcohol/attention study, a ‘sip prime’ procedure provided participants with 25ml of pleasant or devalued (bitter) alcohol. Alcohol urge decreased following devaluation but increased following the pleasant alcohol sip-prime [F(1,62) = 12.1, p=.001]. Following devaluation, proportional alcohol choice [F=32.6, p<.001], number of attention fi xations, and dwell time on alcohol cues decreased [Fs>20.2, ps<.001]. Mediation analysis showed that dwell time on alcohol cues partially mediated the relationship between devaluation and choice behavior [CI95: -20.1, -2.0]. This translational research has shown that 1) alcohol expectancy selectively attenuated goal-directed control of tobacco choice by impairing retrieval of the current value of nicotine; 2) perceived alcohol value can play a role in alcohol- seeking, and attention towards alcohol cues partially mediates this relationship. Attentional bias to substance cues and phasic transitions from goal-directed to habitual control may contribute to relapse by disrupting intentional abstinence. Acknowledgements: Research funded by the Economic and Social Research Council (UK)

S21

FUNCTIONAL MRI OF THE ANXIOGENIC DRUG YOHIMBINE: IMAGING THE NEURAL CIRCUITRY OF STRESS AND ITS PHARMACOLOGICAL MODULATION Gozzi A, Centre for Nanotechnology Innovation @NEST, Ist Italiano di Tecnologia, P.zza S. Silvestro 12, Pisa, 56127, [email protected]

Stress plays a major role in various (patho)physiological processes associated with several psychiatric disorders, including anxiety, depression, schizophrenia, and relapse to drug addiction. In developing translational approaches to study the neural and circuital substrates of stress, it would be advantageous to use stressors that have a similar degree of saliency and homology across species. However, external stressors used in clinical laboratory studies are often unique to humans, and physical stressors akin to those used in animal models are limited by minimal effect size and potential ethical issues. Furthermore, the subjective comparison of such physical stressors in laboratory animals relative to humans is problematic. An experimental approach with clear translational potential is the administration of pharmacological agents known to induce stress states in both humans and animal models. Within this framework, the alpha-2 adrenoreceptor antagonist yohimbine represents a particularly attractive experimental tool, due to its well-documented stress-inducing properties in humans and laboratory species. However, the specifi c neurobiological substrates underlying the anxiogenic effect of this drug remain elusive. In order to begin to address this question, we used pharmacological fMRI (phMRI) to map the neural circuitry engaged by a stress- inducing dose of yohimbine in the rat. A region-specifi c pattern of brain activation was identifi ed, highlighting the recruitment extra-hypothalamic stress neurocircuit (amygdala, BNST, shell of the accumbens) and cortico-striato-thalamic loops involved in compulsive behavioural responses (striatum, cingulate cortex and thalamus). The effect was strongly suppressed by pretreatment with alpha-2-adrenoceptor agonists and dopamine D1 receptor antagonists, thus revealing a permissive role for both norepinephrine and dopamine on the neurofunctional cascade elicited by yohimbine. Importantly, pretreatment with Corticotropin Releasing Factor Type-I (CRF-1) antagonists produced signifi cant response-suppression in the amygdala, striatum, cingulate cortex and somato-sensory cortical areas whilst selective Orexin-1 antagonists highlighted a robust inhibition of fronto-septo-hippocampal regions, together with weaker but signifi cant effects across several regions of the extended amygdala. The differential pattern of inhibition produced by CRF-1 and orexin-1 antagonists suggests that the two neuromodulatory systems may exert their putative anxiolytic effect through distinct neural pathways. Collectively, our fi ndings provide valuable insight into the neural circuitry engaged by the stress-inducing agent yohimbine and its downstream neurochemical determinants. These data strongly support the use of pharmacological stressors in combination with spatially-resolved neuroimaging techniques like fMRI as a translational paradigm for testing pharmacological and neuro-modulatory mechanisms that target stress circuits and effectors. A8 ABSTRACTS

S22

IMAGING THE EFFECTS OF GLUTAMATERGIC MODULATION WITH KETAMINE: PHMRI, FMRI AND QUANTITATIVE PERFUSION Mehta MA, Centre for Neuroimaging Sciences (PO89) Inst of Psychiatry, King’s College London SE5 8AF [email protected] De Simoni S(1), Doyle OM(1), Brammer MJ (1), Zelaya FO (1), Schwarz AJ (2) (1) Dept of Neuroimaging, Inst of Psychiatry, King’s College London (2) Translational Med, Eli Lilly and Co, Indianapolis, Indiana, USA

The effects of NMDA antagonists on brain function can be measured via their effects on task networks or on quantitative blood fl ow. Pharmacological MRI (phMRI) can also be used to examine the MRI signal change after drug infusion and can be used in humans and experimental animals. NMDA receptor antagonists, such as ketamine, induce a phMRI response that may serve as both a CNS index for the modulatory effect of other drugs and a mechanistic pharmacological model to investigate the role of glutamatergic hypofunction in relation to psychiatric disorders. The utility of the phMRI approach depends upon assay fundamentals including an appropriate analysis pipeline, test-retest reliability and sensitivity to different doses of ketamine, as well as robust and replicable pharmacological blockade. We sought to validate these fundamentals in two studies to characterise the test-retest reliability and effect size of the phMRI response to two low doses of ketamine (study I, n=10), and the pharmacological sensitivity to modulation with lamotrigine and risperidone (study II, n=16). BOLD time series data were acquired at rest in healthy volunteers and I.V. ketamine infusion began 5 minutes into the 15-minute scan. Optimised modelling of the phMRI response to ketamine captured robust and reliable changes in BOLD signal, suitable to test dose-ranging pharmacological blockade. The use of quantitative imaging with arterial spin labelling and multivariate modelling was also explored and added to the sensitivity of the analyses and interpretation of the fi ndings. Task related activations in contrast only showed subtle modulations with ketamine. Ketamine phMRI thus represents a promising pharmacodynamic marker in healthy human subjects that may also serve to indicate a “mechanistic” engagement for compounds in early-phase drug development. This study was supported by a grant from Eli Lilly. Additional support was provided by the Innovative Medicines Initiative NEWMEDS award.

S23

LINKING BRAIN MODULATION WITH MEASURES OF FOOD INTAKE AND WEIGHT LOSS IN THE TREATMENT OF OBESITY Nathan PJ, Clinical Unit Cambridge, GSK Clinical Unit, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 2GG UK, CB2 2GG, [email protected] Fletcher PC(2), Napolitano A(1), Dodds C(1), Cambridge V(2), Maltby K(1), Bullmore E(1,2). (1) Medicines Discovery and Development, GSKline, Clinical Unit Cambridge, UK (2) Brain Mapping Unit, Dept of Psychiatry, Univ of Cambridge, UK

Introduction: Obesity is associated with abnormalities in neural mechanisms associated with satiety, motivation, hedonic and cognitive processing. Pharmacological treatments for obesity to date have largely focussed on normalizing these processes. Functional imaging studies have shown abnormal brain activation in obese subjects in response to food or food related cues suggesting its potential use as a biomarker in early clinical development of anti-obesity drugs. However very little is known about the effects of anti-obesity drugs on food related brain activation and if there is a relationship between drug induced modulation of brain activity and subsequent changes in food intake or weight loss. Methods: Independent studies were performed in healthy overweight and obese subjects to examine the effects of two weeks treatment with the serotonin and noradrenaline reuptake inhibitor sibutramine, or the mu-opioid receptor antagonist GSK1521498 (28 days treatment), on brain responses to food cues, food intake and weight loss. Results: Sibutramine attenuated hypothalamic and amygdala responses to food cues, reduced ad libitum food intake and body weight. The sibutramine-induced modulation of the hypothalamic response was correlated with the drug’s impact on both weight and subsequently measured ad libitum eating. GSK1521498 had no effects on weight loss, but reduced hedonic responses to high fat and sucrose dairy products and ad libitum intake of high fat/sugar foods. GSK1521498 also reduced activity in the putamen/pallidum to high vs low reward food cues, although this effect was not correlated with changes in ad libitum food intake. Discussion: Anti-obesity drugs targeting different neural mechanisms perturbed in obesity can attenuate abnormal brain activity associated with processing food or food related cues in areas associated with satiety or reward processing. These fi ndings suggest that functional imaging can be used to test target engagement of candidate anti-obesity drugs. However, the relationship between drug induced modulation of brain activity and corresponding changes in food intake or weight loss was only observed for sibutramine, raising the possibility that the relationship between brain responses and eating behaviour or weight loss may be drug mechanism dependent. Hence, it remains to be established if functional imaging of brain activation to food cues can be used as biomarkers of anti-obesity drug effi cacy in early clinical development to aid decision making.

S24

IMAGING HALLMARKS OF TREATMENT RESPONSE IN MAJOR DEPRESSION Harmer CJ, Psychiatry, Univ of Oxford, Warneford Hospital, Oxford OX3 7JX [email protected]

There is a well-known delay in the clinical effi cacy of conventional antidepressant drug treatments. However, recent evidence suggests that there may be early psychologically-relevant changes which occur more quickly than commonly thought and which support the development of later clinical change (Harmer CJ, Goodwin GM, Cowen PJ (2009) Why do antidepressants take so long to work? A cognitive neuropsychological model of antidepressant drug action. Br J Psychiatry. 195(2):102- 8; Roiser JP, Elliott R, Sahakian BJ. (2012) Cognitive mechanisms of treatment in depression.Neuropsychopharmacology;37:117-36). In particular, depression is characterised by increased processing of negative compared to positive emotional information and these negative biases are believed to play a key maintaining role in the depression cycle. In a recent series of studies, we investigated the early effects of antidepressant drug treatment on behavioural and neural responses to antidepressant drugs. We found that that a single dose of the antidepressant reboxetine was able to reverse negative biases in a sample of depressed patients compared to the double- blind administration of placebo. In particular, a single dose of reboxetine increased the recognition of happy facial expressions, speed to classify positive vs negative personality characteristics and positive emotional memory recall. These kinds of early changes in emotional processing have also been associated with magnitude of later clinical response suggesting that they may play a key role in the clinical effi cacy of these agents. Neuroimaging studies revealed that these early antidepressant effects on emotional processing are associated with modulation of the amygdala, extra-striate cortex and medial prefrontal cortex. A recent study replicated early drug effects on neural markers of emotional processing across centres and found a similar magnitude of effect irrespective of whether or not the participants were experiencing depression symptoms. Such results suggest that these early drug effects are not mediated only via a reversal of aberrant emotional processing but are also able to modify normal brain function. Similar effects on neural markers of emotional processing have been reported with a range of different antidepressant treatments including novel glutamatergic agents and psychological treatments such as Cognitive Behavioural Therapy. As such, early changes in emotional processing circuitry may be a common fi nal pathway for the treatment of depression which is independent, to some extent, from initial treatment modality. This approach may therefore help us to understand how drug treatments are able to reverse psychological symptoms seen in depression and also help generate specifi c hypotheses for stratifi ed treatment approaches and more optimal psychological and pharmacological treatment combinations. Funding The work presented has been funded by the Medical Research Council, AstraZeneca and the P1vital CNS Experimental Medicine Consortium (members AstraZeneca, GlaxoSmithKline, Lundbeck, Organon (a subsidiary of Merck) and Pfi zer). ABSTRACTS A9

S25

ANIMAL MODELS OF LIMBIC CORTICAL DYSFUNCTION IN SCHIZOPHRENIA: IMPLICATION FOR NOVEL TREATMENTS Moore H, Psychiatry, Integrative Neuroscience, Columbia Univ Medical Center (Psychiatry) and The New York State Psychiatric Inst, 1051 Riverside Dr. New York, NY, 10032, [email protected] Gilani A(1), Schobel S(1,2), Chaudhury N(1), Chohan O(1), Ross ME(3), Anderson SA(3), Small SA(2) (1) Columbia Univ Me Ctr, Dept of Psychiatry, 1051 Riverside Dr., New York, NY 10032 USA (2) Columbia Univ Med Ctr, Dept of Neurology, 622 West 168th Street, New York, NY 10032 USA (3) Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065 USA

The temporolimbic cortex, particularly the hippocampus, is consistently altered in schizophrenia. This is evidenced at a number of levels from altered gene expression and histopathology assessed postmortem to gross structural defi cits and abnormal activity assessed in vivo with functional imaging methods. These abnormalities, particularly those assessed in vivo, correlate with specifi c symptoms and cognitive abnormalities in schizophrenia patients. Moreover, abnormal hippocampal activity can precede and predict the fi rst psychotic break in at-risk individuals. This talk will provide an overview of rodent studies illustrating 1) multiple pathogenic pathways to hippocampal hyperactivity and hypomorphism, and 2) the possible role(s) of the hippocampus in driving a number of schizophrenia-relevant neurochemical, behavioral or cognitive phenotypes. I will describe fi rst a study in which we have aimed to model the impact of a partial interneuron defi cit in the hippocampus. Here, we have used mice with mutations of genes expressed within the embryonic medial ganglionic eminence that disrupt cortical interneuron development. I will focus on the cyclin D2 null mouse, a model showing a partial and persistent defi cit in the density of parvalbumin-expressing neurons, but not other interneuron subtypes, within the hippocampus, as well as an equivalent defi cit in inhibitory synaptic input onto hippocampal projection neurons. This defi cit in synaptic inhibition within the hippocampus corresponds with an increase in basal metabolic activity, measured in vivo with functional imaging methods similar to those applied clinically. Additional psychosis-relevant phenotypes associated with impaired hippocampal inhibition in this disease model include an up-regulation of dopamine neuron activity, an increased behavioral response to amphetamine, and abnormalities in hippocampally-mediated cognition. These data establish the plausibility of a causal link between hippocampal interneuron defi cits and the hyper-metabolic state in this region that has been reported to correlate with psychotic symptoms in schizophrenia and its risk states. These fi ndings will be compared to studies of other perturbations, including acute and chronic NMDA receptor blockade, that can also lead to hippocampal hyperactivity, and the following hypothesis will be explored: There is a cluster of schizophrenia-relevant phenotypes – increased metabolic activity in the hippocampus (as assessed functional MRI or metabolic PET imaging), increased presynaptic markers of meso-striatal dopamine neurotransmission (as assessed with neurochemical PET imaging), increases in the neurochemical or behavioral response to amphetamine, and defi cits in temporal-lobe-mediated cognition - that can result from a dysregulation of hippocampal projections to their cortical and basal ganglia targets. Moreover, there are multiple pathogenic pathways to this dysregulated state.

S26

THE EFFECTS OF CANNABIS ON THE BRAIN: IN VIVO STUDIES OF THE DOPAMINERGIC AND CANNABINOID SYSTEMS AND THE LINK TO PSYCHOTIC AND AFFECTIVE SYMPTOMS Howes OD, Psychiatric Imaging, MRC Clinical Sciences Centre and Inst of Psychiatry, Hammersmith Hospital, London W12 0NN [email protected]

Introduction: The mechanisms that mediate the effects of cannabis on the brain are unknown but preclinical studies implicate the dopaminergic and cannabinoid systems. We used functional imaging to investigate the effects of cannabis and one of its active constituents, delta-9-THC, on these systems. Method: In the fi rst study we used [18F]-DOPA PET to compare dopaminergic function in regular cannabis users (n=19; median use= 26 days/month; median time to consume 1/8th oz cannabis=4 days; mean (SD) age=20.8 (1.7) years) with that in matched non-user controls (n=19; mean (SD) age=22.3 (2.8) years), and then measured the severity of psychotic symptoms induced after they smoked cannabis. In the second study we used multi-modal imaging with [11C]-MePPEP PET to measure cannabinoid receptor-1 (CB-1) availability, and functional Magnetic Resonance Imaging (fMRI) to measure the effects of 10mg delta-9-THC (similar to the amount of THC in one cannabis cigarette) on fear processing in healthy non-user volunteers (n=14; mean (sd) age=23.8 (4.5) years) in a placebo-controlled randomized, double-blind within-subjects design. During the fMRI sessions, participants were shown faces exhibiting fearful and neutral expressions and were asked to indicate the gender of the face stimuli by pressing a button. We compared the effects of delta-9-THC and placebo on the amygdalar response to fearful relative to neutral faces. Results: Dopamine synthesis capacity was signifi cantly reduced in cannabis users (mean (sd) Kicer = 0.0127 (0.001)/ min) compared to matched healthy controls who had never used cannabis (mean (sd) Kicer = 0.0134 (0.001)/ min; t(36)=2.54, p=0.016), with a cohen’s d effect size of 0.8. Greater reduction in dopaminergic function was linked to greater use of cannabis (r=+0.77, p<0.001). Dopamine synthesis capacity was lowest in the cannabis users who met dependence/abuse criteria (n=10; mean(SD) Kicer = 0.0124 [0.0004]/min) and was signifi cantly lower than cannabis users who did not meet these criteria (n=9; mean (sd) Kicer =0.0131 [0.0007]/min; t(17)=2.80, p=0.012). However, there was no relationship between dopaminergic function and the severity of psychotic symptoms induced by cannabis (r=0.32, p=0.2). In the second study delta-9-THC signifi cantly increased subjective ratings of anxiety (chi2=7.1, p=0.008) relative to the placebo condition. CB-1 receptor availability in the amygdala was directly related to the effects of THC on fear processing in the amygdala (r=+0.5, p<0.05), and to the severity of anxiety symptoms induced by THC (r=+0.5, p<0.05). Conclusions: These fi ndings suggest that 1) regular cannabis use is associated with altered dopaminergic function with a large effect size (d=0.8); 2) alterations in the dopamine system are NOT linked to the induction of psychotic-like symptoms by cannabis; but rather 3) variation in the vulnerability to the effects of the cannabis constituent, THC, is mediated by the CB1 receptor system in the amygdala through altering sensitivity to THC effects on emotional processing. This work was funded by the MRC UK

S27

COGNITIVE ENHANCEMENT IN SCHIZOPHRENIA Sahakian BJ, MRC/Wellcome Trust Behavioural and Clinical Inst, Univ of Cambridge, Addenbrooke’s Hospital Site, Cambridge CB2 2QQ [email protected]

Psychotic disorders are debilitating mental illnesses characterised by disorganised thoughts and speech, hallucinations, delusions, and cognitive and emotional impairments. Cognitive impairments are common, often appearing before the onset of the psychotic syndrome and contribute to poor functional outcomes. People with schizophrenia have abnormalities in attention, memory, verbal processes, impulsivity and executive functions, and defi cits are present in fi rst episode psychosis (FEP), often before a formal diagnosis of schizophrenia can be established. Abnormalities in working memory have been observed at all stages of the illness. This series of studies investigates the effects of modafi nil on cognition in patients with fi rst episode psychosis and patients with schizophrenia who are high functioning (Scoriels L, Barnett JH, Soma PK, Sahakian BJ, Jones PB. (2011a). Effects of modafi nil on cognitive functions in fi rst episode psychosis. Psychopharmacology, 220(2):249-58; Scoriels L, Barnett JH, Murray GK, Cherukuru S, Fielding M, Cheng F, Lennox BR, Sahakian BJ, Jones PB (2011b). Effects of Modafi nil on Emotional Processing in First Episode Psychosis. Biol Psychiatry., 69(5), 457-464; Turner DC, Clark L, Pomarol-Clotet E, McKenna P, Robbins TW, Sahakian BJ (2004). Modafi nil improves cognition and attentional set shifting in patients with chronic schizophrenia. Neuropsychopharmacology, 29, 1363-1373). Findings demonstrated enhanced cognitive fl exibility with modafi nil in patients with schizophrenia. Modafi nil also improved the recognition of emotional faces in patients with fi rst episode psychosis. In addition, modafi nil improved working memory in these patients. Scoriels et al (2011b) showed for the fi rst time that modafi nil improved working memory, a core cognitive defi cit in the fi rst episode of psychosis, which remains substantially impaired in schizophrenia. Given the known associations between cognition and functional outcomes in schizophrenia, it is possible that the improvement in working memory induced by modafi nil could have a signifi cant benefi cial effect on broader aspects of patients’ functioning, including functional outcome, quality of life and wellbeing. In this respect, pharmacological cognitive enhancement may be most benefi cial if implemented early in the disorder, prior to chronic cognitive dysfunction and severe impacts on functioning and quality of life (Scoriels L, Barnett JH, Murray GK, Cherukuru S, Fielding M, Cheng F, Lennox BR, Sahakian BJ, Jones PB (2011b). Effects of Modafi nil on Emotional Processing in First Episode Psychosis. Biol Psychiatry., 69(5), 457-464). Financial support was received from the Stanley Medical Research Institute and the Pinsent Darwin Fund of Cambridge University to Peter Jones and Linda Scoriels, respectively. Barbara Sahakian’s work was funded by the Wellcome Trust (Program Grant Ref 089589/Z/09/Z) and by the MRC and the Wellcome Trust to the Behavioural and Clinical Neuroscience Institute (MRC Ref G1000183; WT Ref 093875/Z/10/Z). A10 ABSTRACTS

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GENETIC DATA IMPLICATE SPECIFIC ABNORMALITIES OF SYNAPTIC FUNCTION IN THE PATHOGENESIS OF SCHIZOPHRENIA Owen MJ, MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Inst, Cardiff Univ, Henry Wellcome Bldg, Heath Park,

Cardiff CF14 4 XN [email protected] Introduction: Schizophrenia is highly heritable and predisposition is conferred by a large number of risk alleles, some common, others rare. Rare variants which confer high individual risks of illness are of particular interest since they are particularly suitable for informing the design of animal and cellular models. Genome-wide studies have shown that copy number variants (CNVs) are one class of rare variant that substantially increase susceptibility to schizophrenia. Recently it has become possible to conduct unbiased genome-wide studies to detect rare single nucleotide variants (SNVs) and small insertion/deletions (indels) conferring high risk of illness. Given the low fecundity of schizophrenia we postulated that de novo mutations are particularly likely to be relevant to pathogenesis. Methods: I will report data from two studies aimed at detecting de novo mutations in 662 schizophrenia parent proband trios. All patients had been hospitalised and were recruited from psychiatric services and all met DSMIV criteria for schizophrenia or schizoaffective disorder based upon SCAN interview by psychiatrists, and review of case notes. In the fi rst study CNVs were detected using Affymetrix 6.0 arrays and in the second, ongoing study whole exome sequencing is being conducted. Results: We found that de novo CNVs occurred in 5.1% of 662 schizophrenia probands and were enriched for known and novel pathogenic loci. The occurrence of multiple de novo CNVs implicated EHMT1 as well as DLG2, whose orthog is directly regulated in Drosophila by the orthlog of EHMT1, and other members of the membrane-associated guanylate kinase (MAGUK) family of proteins. Genes within the de novo CNVs were signifi cantly enriched for membership of the postsynaptic density (PSD; p=1.72 x 10-5) largely as a consequence of enrichment for membership of N-Methyl-D-Aspartate receptor (NMDAR; p=1.30x10-5) and neuronal activity-regulated cytoskeleton-associated protein complexes (ARC; p=1.07x10-6). I will also present preliminary data from whole exome sequencing implicating deleterious SNVs affecting the same protein complexes. Conclusions: These fi ndings provide strong evidence that specifi c synaptic complexes implicated in cognitive function and neuronal plasticity are highly enriched for rare mutations that contribute to schizophrenia pathogenesis.

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EPIGENETICS AND PSYCHIATRIC DISORDERS Hall J, Div of Psychiatry, Univ of Edinburgh, Kennedy Tower, Royal Edinburgh Hospital, Edinburgh EH10 5HF [email protected]

In this talk I will outline evidence that supports the view that epigenetic processes play an important role in the development of psychiatric illnesses and may provide an important new means of treatment. I will initially review clinical epidemiological data pointing to the importance of pre-natal and early post-natal events in infl uencing risk for later mental disorder. I will then link this to pre-clinical and clinical evidence that epigenetic processes may, at least in part, underlie these associations. Finally I will highlight evidence that suggests that drugs which alter epigenetic marks may have clinical utility in psychiatric disorders. Jeremy Hall is supported by an SFC Scottish Senior Clinical Fellowship.

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BEHAVIOURAL EPIGENETICS; EXCITING BUT UNCERTAIN PROSPECTS Wilkinson LS, Schools of Psychology and Medicine, Cardiff Univ, Tower Bldg, Park Place, Cardiff CF10 3AT [email protected]

In the broadest sense epigenetics refers to gene effects that are not directly related to gene sequence (that’s genetics) and which usually impact on function by changes in the spatial and temporal pattern of gene expression. There are a number of molecular mechanisms mediating epigenetic effects on gene expression, notably DNA methylation and post-translational modifi cations of histone proteins that lie in close proximity to DNA as part of the chromatin complex. Recently it has become apparent that epigenetic mechanisms can infl uence brain and behavioural functioning across a rapidly increasing range of areas, including brain development, enduring effects of early life experience and addiction. These fi ndings have encouraged speculation about how important the burgeoning fi eld of ‘behavioural epigenetics’ may turn out to be in the aetiology and possible treatment of neurological and psychiatric disorders, and additionally the extent to which epigenetic mechanisms represent plausible biological substrates of gene, environment interplay effects. However, the fi eld of behavioural epigenetics is at an early stage and many fundamental questions remain to be addressed if we are to make practical use of the initial fi ndings. In human work, how are we going to overcome the ‘surrogate tissue’ problem, whereby fi ndings in peripheral tissues such as blood, whilst fi ne for genetics, may not be valid proxies for epigenetic changes in brain? How can the environment signal to chromatin to alter gene expression in brain, and how might molecular marks left by the environment (and consequent vulnerabilities) be transmitted to future generations? Currently, ‘epipharmaceuticals’ targeting brain are crude. How are we ever going to achieve the necessary degree of specifi city to be able to infl uence discrete circuitries and pathways in brain using drugs? ABSTRACTS A11

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EPIGENETICS OF THE IMPACT OF EARLY TRAUMA ON BEHAVIOR ACROSS GENERATIONS Mansuy I, Brain Research Institute, Univ/ETH Zürich, Wintherthurerstrasse 190 , 8057 [email protected] This will be presented by Johannes Bohacek.

The development and expression of behaviors in mammals are strongly infl uenced by environmental factors. When favorable and positive, these factors can facilitate appropriate responses and normal behaviors, but when aversive and stressful, they can lead to behavioral pathologies. Adverse and traumatic events early in life are particularly strong risk factors for behavioral and psychiatric conditions such as depression, personality and conduct disorders, and antisocial behaviors. Such disorders can not only affect the individuals directly exposed to trauma, but can also be transmitted and similarly expressed in the following generations (Franklin, T. B. & Mansuy, I. M. Epigenetic inheritance in mammals: evidence for the impact of adverse environmental effects. Neurobiol Dis 39, 61-65 (2010). The mechanisms underlying the etiology and inheritance of behavioral symptoms induced by traumatic stress early in life have been proposed to involve epigenetic processes, but remain undefi ned. This talk will discuss an experimental model of early traumatic stress in mice that provides initial evidence for the contribution of epigenetic processes to the inherited impact of stress on behavior. This model shows that chronic and unpredictable maternal separation causes depressive- and impulsive-like behaviors, social withdrawal and cognitive defects in adult mice, and that these symptoms are transmitted to the following offspring. It provides initial evidence that these alterations are associated with persistent changes in DNA methylation in the promoter-associated CpG island of several genes, in the brain of the offspring and in the germline of their stressed fathers (Franklin TB, Linder N, Russig H, Thony B, Mansuy IM. Infl uence of early stress on social abilities and serotonergic functions across generations in mice. PLoS One 6, e21842 (2011); Franklin TB et al. Epigenetic transmission of the impact of early stress across generations. Biol Psychiatry 68, 408-415 (2010); Weiss IC, Franklin TB, Vizi S, Mansuy IM Inheritable effect of unpredictable maternal separation on behavioral responses in mice. Front Behav Neurosci 5, 3 (2011). These fi ndings suggest that epigenetic mechanisms contribute to the impact of negative environmental conditions early in life on adult behavior and its inheritance (Franklin TB & Mansuy IM. The prevalence of epigenetic mechanisms in the regulation of cognitive functions and behaviour. Curr Opin Neurobiol 20, 441-449 (2010); Franklin TB & Mansuy IM The involvement of epigenetic defects in mental retardation. Neurobiol Learn Mem 96, 61-67 (2011); Gräff J & Mansuy IM Epigenetic codes in cognition and behaviour. Behav Brain Res 192, 70-87 (2008); Gräff J & Mansuy IM Epigenetic dysregulation in cognitive disorders. Eur J Neurosci 30, 1-8 (2009).

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THE EPIGENETICS OF COMPLEX PSYCHIATRIC DISORDERS - NOVEL TREATMENT TARGETS? Mill J, Box P80 / 82 Inst of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF [email protected]

Given the high heritability estimates for most complex neuropsychiatric disorders, current approaches to understanding etiology have primarily focussed on uncovering a genetic contribution to disease-onset. Despite the discovery of a number of novel susceptibility loci for disorders including depression, schizophrenia and autism using genome-wide association approaches, these loci account for only a small proportion of attributable risk and the mechanism behind their action remains unknown. There is growing recognition that epigenetic mechanisms are important in the etiology of complex disease, acting at the interface between the genome and the environment. Recent technological advances mean that it is now feasible to study epigenetic marks such as DNA methylation at base-pair resolution across the genome. In this talk I will present data from our group showing how dynamic epigenetic processes are involved in neuropsychiatric phenotypes, and can be infl uenced by environmental, genetic and stochastic factors. I will describe results from ongoing studies of disease-associated epigenetic changes using post-mortem brain material, discordant monozygotic twins and clinical samples. Finally, I will review the evidence that many psychiatric drugs are known to infl uence the epigenome; given the reversible nature of epigenetic processes they represent potential targets for the development of novel therapeutic agents.

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“JUST CAN’T STOP MYSELF”. OCD VERSUS ADDICTION: CLINICAL ASPECTS. Fineberg NA, National OCD Treatment Service, Hertfordshire Partnership NHS Foundation Trust , Queen Elizabeth II Hospital, Welwyn Garden City AL7 4HQ. naomi. fi [email protected] Gale T(1), Sharma P(2), Angst J(3). (1) Hertfordshire Partnership NHS Foundation Trust, Queen Elizabeth II Hospital, Welwyn Garden City AL7 4HQ. (2) Mott House, St Bernard’s Unit West London Mental Health NHS Trust Uxbridge Road Southall UB1 3EU (3)Psychiatrische Universitätsklinik Lenggstr.31, Postfach 1931 CH-8032 Zurich Switzerland

Obsessive compulsive disorder (OCD) is a disabling, early-onset psychiatric disorder. It is characterised by obsessions, constituting a narrow repertoire of recurrent, unwanted thoughts that usually predict an unpleasant event (e.g. contamination by asbestos) and compulsions, constituting repetitive, time-consuming, stereotyped behaviours, usually designed to reduce the negative consequences associated with the obsessions ( e.g. washing/checking rituals). Patients experience an unpleasant and irresistible urge to perform the compulsive act and as the feared consequence almost never occurs, this behaviour is subject to considerable reinforcement. Thus, compulsions are designed to reduce or prevent discomfort. Addictive behaviours, on the other hand, represent the result of an overwhelming drive to undertake a repetitive act that is, to some extent, rewarding. In addition to psychoactive substance abuse, ‘behavioural addictions’, such as pathological gambling and compulsive internet- usage, are increasingly recognised as a major public-health concern. In the course of addiction, tolerance to the reward increases and the addicted person continues to repeat the behaviour in an attempt to avoid or reduce unpleasant cravings and/or withdrawal-effects. Thus, addiction changes into compulsion over time. Moreover, in the course of OCD, compulsions become dominant and may develop a habit-like or even a quasi-rewarding quality. A drive to develop better treatments is fuelling clinical and neuroscientifi c interest in the relationship between compulsive and addictive states. Evidence that individuals with OCD and stimulant-dependence or trichotillomania (impulse-control disorder) show overlapping neurocognitive and neuroimaging biomarkers are mirrored by the fi nding of overlapping comorbidity in clinical cohorts. However, such data is subject to considerable selection-bias. A recent large-scale case-control family-based study was unable to show a direct association between OCD and substance abuse or other impulse-control disorders (pathological gambling, pyromania, kleptomania) (Bienvenu OJ, et al., Psychol Med. 2012 Jan;42(1):1-13). Addiction to tobacco shows a reduced prevalence in OCD and is associated with increased clinical impulsivity. The Zurich cohort studies show an association between OCD and sub-threshold OC states and substance abuse only in the presence of bipolar comorbidity. It is therefore possible that comorbid OCD-addiction represents a clinically-relevant, highly-impulsive OCD-subgroup. Major differences in treatment-response separate OCD and addiction; whereas OCD responds to SSRI and cognitive-behaviour therapy, substance and behavioural addictions are relatively treatment-refractory, though some success has been reported with naltrexone, which appears ineffective in ‘pure’ OCD. Memantine and mood stabilisers e.g. topiramate show limited effi cacy in OCD and some forms of addiction. These compounds merit further evaluation in OCD-addiction. A12 ABSTRACTS

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MAPPING THE OVERLAP. COGNITIVE AND IMAGING ENDOPHENOTYPES OF OCD AND ADDICTION Chamberlain SR, Dept of Psychiatry, Univ of Cambridge, Level E4, Addenbrooke’s Hospital, Cambridge, CB0 0QQ [email protected] Ersche K(address as above)

Introduction: The repetitive symptoms of certain psychiatric conditions, such as obsessive-compulsive disorder (OCD), share parallels with symptoms of substance addiction. In OC spectrum disorders, as with substance addiction, there can be initial impulses (unplanned acts deleterious to long term outcomes), evolving through repetition into compulsive habits that are ingrained and diffi cult to resist. Viewing OC spectrum disorders as candidate ‘behavioural addictions’ may offer new insights. Methods: Neurocognitive tasks germane to addiction, along with structural and functional magnetic resonance imaging, were undertaken in patients with OCD, patients with substance dependence (principally stimulant dependence), and in control volunteers with no known family history of either condition. Clinically unaffected fi rst- degree relatives of patients were also similarly assessed. Results: There was overlap in the neurocognitive profi les of OCD and substance addiction, quantifi ed using objective cognitive tests dependent on fronto-striatal circuitry. Impaired response inhibition occurred across both disorders and was also evident in unaffected patient relatives at risk. These defi cits were associated with distributed neural abnormalities, particularly implicating the right inferior frontal gyrus. Certain personality traits were also identifi ed in patients and their unaffected relatives, such as heightened subsyndromal obsessive-compulsive personality disorder traits in OCD, and heightened Barratt Impulsivity scores in substance addiction. Conclusions: These data are consistent with the notion of partially overlapping neurobiology between OCD and substance addiction, and suggest that certain abnormalities also occur in patients’ unaffected relatives and thereby represent candidate endophenotypes. Findings have implications for conceptualising OC spectrum disorders and identifying novel therapeutic directions for conditions that are often refractory to existing fi rst-line interventions.

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NOVEL PHARMACOLOGICAL TREATMENTS FOR PATHOLOGICAL GAMBLING AND RELATED ADDICTIVE DISORDERS Grant JG, Psychiatry, Univ of Minnesota, 2450 Riverside Avenue Minneapolis, MN USA 55454 [email protected]

Introduction: An estimated 1-5% of the world’s population has a problematic form of gambling behavior. Psychosocial problems are common among gamblers and include signifi cant fi nancial and marital problems, reduced quality of life and impaired functioning. The repeated engagement in gambling can be conceptualized as the result of an imbalance between urge and inhibition, consistent with increased activity in the mesocorticolimbic dopamine system (reward) and decreased activity in cortical inhibitory processes. Opioid antagonists have been hypothesized to infl uence dopamine neurotransmission in the nucleus accumbens, dampening addiction-related excitement and cravings. Preclinical studies have suggested that levels of glutamate within the nucleus accumbens mediate reward-seeking. Catechol-O-methyl-transferase (COMT) inhibitors represent a novel pharmacological strategy targeting inhibitory dysfunction in the prefrontal cortex. COMT inhibitors increase extracellular levels of dopamine in the prefrontal cortex to increase response fl exibility and inhibition. Methods: Data from treatment studies of pathological gambling will be presented. Double-blind, placebo-controlled trials of naltrexone and nalmefene (both opioid antagonists) in the treatment of 606 subjects with pathological gambling will be presented. Double- blind data on the use of N-acetyl cysteine, a glutamatergic agent acting in the nucleus accumbens, has been studied in 67 subjects with gambling and co-occurring nicotine dependence. One study examining a COMT inhibitor (n=14) will also be presented. Clinical characteristics, neurocognition, neuroimaging, and genetics data have been examined in conjunction with treatment trials as means by which to understand treatment response. Results: Double-blind, placebo-controlled studies of opioid antagonists have demonstrated effi cacy in reducing the intensity of urges to gamble and gambling behavior (signifi cant improvement was seen in 75% of opioid antagonist subjects compared to 24% of placebo subjects). A positive family history of addiction predicted response to opioid antagonists. N-acetyl cysteine, an amino acid and glutamate modulating agent, demonstrated positive effects on urges and gambling behavior. Tolcapone, a COMT inhibitor, was associated with statistically signifi cant reductions on measures of gambling severity (mean scores reduced from 22.5 to 9.2; p<.001). Preliminary data from TOL fMRI task showed improved planning with tolcapone treatment (as indexed by response times) and that the improvement in response times signifi cantly correlated with improvement in symptom severity. 100% of subjects with the val/val COMT polymorphism reported signifi cant improvement in gambling symptoms. Conclusions: Research on the pharmacological treatment of pathological gambling appears when a clear pathophysiology is targeted. Neurocognitive, neuroimaging, and genetics represent promising options to further understand who may benefi t most from any pharmacological option. Dr. Grant has received research grants from National Institute on Drug Abuse (RC1-DA028279-01), Forest Pharmaceuticals, Transept Pharmaceuticals, and Psyadon Pharmaceuticals. Dr. Grant holds a patent for the use of COMT inhibitors in the treatment of impulse control disorders.

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ZEBRAFISH MODELS OF LOCOMOTOR ACTIVITY AND IMPULSIVITY Lesch KP, Div of Molecular Psychiatry, ADHD Clinical Research Network, Lab of Translational Neuroscience, Dept of Psychiatry, Psychosomatics a Univ of Wuerzburg, Fuechsleinstr. 15 Wuerzburg, Germany 97080 [email protected] Lange M(1), Bally-Cuif L (1), Norton W(1) (1) Zebrafi sh Neurogenetics Group, Lab of Neurobiology and Development (N&D), CNRS UPR 3294, Inst of Neurobiology Alfred Fessard, Avenue de la Terrasse, Gif-sur-Yvette cédex, France

Developmentally inappropriate hyperactivity, inattention, increased impulsivity and motivational/emotional dysregulation are characteristics of attention-defi cit/ hyperactivity disorder (ADHD), a common, early onset and enduring neuropsychiatric disorder. ADHD displays similar prevalence rates throughout different cultural settings, resulting in impairments of learning performance in scholastic settings as well as in multiple other domains of personal and professional life. ADHD has long been considered a disorder of childhood that resolves gradually with maturation during adolescence but this view was contested by systematic follow-up studies documenting remarkable persistence of ADHD into adulthood associated with considerable risk for psychiatric co-morbidity such as depression, anxiety, obsessive- compulsive behaviour, and substance use as well as failure in psychosocial adaptation. The substantial heritability of ADHD is well documented and recent genome-wide risk gene analyses revealed synaptic cell adhesion molecules (e.g. latrophilin-3, LPHN3; fi bronectin leucine-rich repeat transmembrane protein-3, FLRT3), glutamate receptors (e.g. metabotropic glutamate receptor-5, GRM5) and mediators of intracellular signalling pathways (e.g. nitric oxide synthase-1, NOS1). These genes encode principal components of the molecular machinery that connects pre- and postsynaptic neurons, facilitates glutamatergic transmission, modulates glutamate-dopamine system crosstalk, controls synaptic plasticity and empowers intersecting neural circuits to process and refi ne information. Given the currently high rate of gene discovery it is a desiderate to develop animal models of this disease in order to better understand its aetiology and improve the treatment options that are available. Here, I will explore how we can develop zebrafi sh as a translational model for ADHD. In order to validate the link between the adhesion-G protein-coupled receptor LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafi sh development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry. ABSTRACTS A13

MA01

PERFORMANCE IN AN INSTRUMENTAL SUCCESSIVE NEGATIVE CONTRAST TASK BY WISTAR RATS WITH AN ANXIETY-LIKE PHENOTYPE Mitchell EN, School of Physiology and Pharmacology, Univ of Bristol, Medical Sciences Bldg, University Walk, Bristol BS8 1TD [email protected] Marston HM(2), Nutt DJ(3), Lodge D(1), Robinson ESJ(1) (1)School of Physiology & Pharmacology, Univ of Bristol, University Walk, Bristol, BS8 1TD UK. (2)TPP Global Development, 10 York Place, Edinburgh, EH1 3EP, UK. (3) Neuropsychopharmacology Unit, Div of Experimental Medicine, Imperial College, Burlington Danes Bldg, Hammersmith Hospital, London W12 0NN, UK.

Evaluation of behavioural changes in response to reward gain or loss has been hypothesised to refl ect underlying affective state in animals. We have previously demonstrated a successive negative contrast (SNC) effect using an operant SNC task and found this effect is attenuated by anxiolytic drug treatment (Mitchell et al, Supplement to Journal of Psychopharmacology, vol 25. Supplement to no. 8, A51). In this study we investigated the SNC effect in the UoB Han (formerly B&K) Wistar strain, which lacks the mGluR2 receptors and exhibits an anxiety-like profi le in the open-fi eld and elevated plus maze assays (Ceolin et al, 2011. The Journal of Neuroscience. 31(18):6721-6731). Male Wistar rats (n=12 per group; UoB Han and Charles River, control animals) were trained to respond to a visual cue with nose-poke responses to receive a four pellet reward. Once trained, the SNC effect was investigated using a series of devalue sessions where animals received only a single pellet outcome for each correct response. After a week re-baseline, animals were then exposed to 10 days of testing with the lower reward value. In the initial devalue sessions, a signifi cant SNC effect was observed for both groups. There was a trend towards a strain difference for correct latency (p=0.065) with the UoB Han animals being slower to respond to the cue although not signifi cantly different on other measures. In the 10 repeated devalue sessions there was a signifi cant devalue effect across the study. There was also a signifi cant main effect of group (F(1, 20)=5.642; P=0.028) where the UoB Han animals were slower to respond to the cue. A signifi cant DAY*GROUP interaction for collection latency was seen (F(5.8, 115.6)=3.011; P=0.01) where the UoB Han rats showed an enhanced contrast effect. These data indicate a difference in SNC effect between the UoB Han and CR rats which may relate to their anxious phenotype. These data support our hypothesis that the SNC effect is potentiated under conditions of increased anxiety. ESJR is an RCUK Academic Fellow supported by the British Pharmacological Society Integrative Pharmacology Fund EM is funded by the BBSRC and MSD

MA02

FROM RODENTS TO PATIENTS: PREFRONTAL COGNITIVE AND HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS FUNCTION FOLLOWING TRAUMA EXPOSURE Lapiz-Bluhm MD, Family and Community Health Systems, Univ of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, 78229 [email protected]

Introduction: Increasing evidence supports the involvement of the prefrontal cortex in the development of stress-related disorders. We have shown that chronic stress exposure in rats impairs their performance in the attentional set-shifting task (Lapiz-Bluhm et al. (2008), J. Neuroendocrinology, 20, 1115-1137). Translating these results to humans, we investigated the set-shifting ability of individuals who have been exposed to trauma and have PTSD symptoms. Characterized by intrusive recollections (re-experiencing), avoidance/numbing and hyper-arousal, PTSD has been associated with a dysfunction in prefrontal cortical function and changes in hypothalamic- pituitary adrenal (HPA) axis activation. The nature of these associations is not fully understood. This study aims to characterize the prefrontal cognitive function and HPA modulation of individuals with PTSD symptoms. Methods: Individuals (N=36) who experienced trauma in the past 12 months and normal healthy controls completed a demographics survey, PTSD Symptom Scale-Interview (PSSI), and the computerized version of the Wisconsin Card Sorting Test (WCST), a clinical cognitive test for executive prefrontal function. The WCST measures were categories completed, trials to complete fi rst category, perseverative errors, total errors, conceptual level responses, and failure to maintain set. Subjects collected salivary samples at 6 time points: 1) early evening; 2) before bed); 3) at wake-up; 4) 30 minutes after wake-up; 5) mid-morning, and 6) early evening for 3 consecutive days. Samples were analyzed for cortisol and dihydroepiandrosterone (DHEA) levels. Data were analyzed with signifi cance set at p<0.05. Results: The demographics between the trauma-exposed group and controls were comparable. Trauma-exposed individuals scored signifi cantly higher in the PSSI compared to controls (t=6.21, p<0.001) and completed signifi cantly less number of categories in the WCST (t=-2.31, p=0.03). ANOVA analysis of preliminary cortisol data indicated a signifi cant Group X Time interaction (F= 59.40, p<0.05), with early morning cortisol higher in trauma-exposed individuals with PTSD symptoms (p<0.05). DHEA data indicated a signifi cant Group (p<0.05) and Time (p<0.05) effects, and a Group X Time interaction (F= 250.70, p <0.05), with signifi cantly higher early morning DHEA (wake-up and 30-min after) in individuals with PTSD symptoms (p<0.05). Conclusion: PTSD symptoms were associated with impairment in set-shifting ability in the WCST and a differential cortisol and DHEA activation. The results provide further support towards the involvement of the prefrontal cortex and the HPA axis in PTSD. These data may inform strategies to treat, or even prevent, PTSD. Funding: Hogg Foundation for Mental Health Research and the Institute for the Integration of Medicine and Science KL2RR025766 and 1UL1RR025767-03

MA03

EFFECT OF TRYPTOPHAN SUPPLEMENTATION ON THE CORTISOL RESPONSE TO SOCIAL STRESS IS MODULATED BY 5-HTTLPR GENOTYPE Cerit H, Inst of Psychology, Clinical, Health and Neuropsychology Unit, Leiden Univ, Pieter de la Court Bldg Wassenaarseweg 52, 2333 AK Leiden The Netherlands [email protected] Van der Does AJW (1), Jans LAW (1) (1) Faculty of Social and Behavioural Sciences, Pieter de la Court Building, Wassenaarseweg 52, 2333 AK Leiden, The Netherlands.

Background: The serotonin transporter (5-HTT) membrane protein is essential in regulating the concentration of 5-HT in the synaptic cleft. The 5-HTT is encoded by the SLC6A4 gene, and transcriptional activity of this gene is regulated by the 5-HTT-linked polymorphic region (5-HTTLPR). Two major variants of the 5-HTTLPR exist, with functional signifi cance in that the short (S) allele of the 5-HTTLPR is associated with less transcriptional effi ciency and less 5-HTT expression than is the long (L) allele (Lesch et al., 1996, Science 274: 1527-1531). Several studies have found that 5-HT function and 5-HTTLPR genotype affect HPA-axis reactivity to social stress; however, the direction of this interaction has yet to be conclusively established (Mueller et al., 2011, Neuropsychopharmacology 36: 1332-1339). The relationship between the 5-HTTLPR genotype and HPA-axis reactivity has been examined by manipulating tryptophan (TRP) levels in healthy S’/S’ and L’/L’ carriers (Markus&Firk, 2009, Neuropsychopharmacology 34: 2667-2674). They didn’t fi nd an effect of a single dose TRP administration (0.8 g) on cortisol response after a stressor in either of the genotype groups. In the present study, we examined the effect of six days TRP administration on reactivity of the HPA-axis, specifi cally investigating whether its role is modulated by genetic variation in the 5-HT system. Methods: In a double-blind parallel design, 25 S’/S’ and 21 L’/L’ carriers were randomized to take l-tryptophan (2.8 g/d) or placebo supplements for six days. At day 7 all participants were exposed to the Trier Social Stress Task (TSST; Kirschbaum et al., 1993). Salivary cortisol and subjective mood states were monitored before, during and after TSST exposure at six time points. Results: RM-GLMs conducted in S’/S’ and L’/L’ groups separately on cortisol concentrations revealed that S’/S’ carriers who took l-tryptophan supplements had a lower cortisol response to stress than S’/S’ carriers who took placebo (F(1.50, 33.07) = 3.55, p = .052, ηp2= .139). Tryptophan had no effect on cortisol in L’/L’ carriers and no effect on subjective mood states in either genotype group. Conclusion: Tryptophan attenuates the cortisol response to social stress depending on the 5-HTTLPR genotype. S’/S’ carriers may be more reactive to 5-HT manipulations. Future studies may investigate how the effects of TRP supplements on the cognitive, physiological and behavioural levels depend on serotonergic genotypes. Research on TRP supplementation in individuals with serotonergic genotypes conferring vulnerability to stress might give new insights in personalized treatment of mood disorders. Financial Disclosures: This research was funded by VICI grant # 453-06-005 from the Netherlands Organization of Science (N.W.O.-MaGW) to AJWVdD. AJWVdD has received a consultancy fee from Hoffmann – La Roche Ltd (unrelated to present research). HC and LAWJ have no fi nancial interests to disclose. A14 ABSTRACTS

MA04

USING 7.5% CO2 CHALLENGE TO EVALUATE NOVEL PSYCHOLOGICAL TREATMENTS FOR ANXIETY De Carvalho F, Medicine, Univ of Southampton, Medicine, Univ of Southampton, SO171BJ, [email protected] O’Halloran K (1), Chong J (1), Morris JL (2), Girling N (2), Ainsworth B (2), Marshall J (2) , Sargaent E (2), Pinkney V (2), Miler J (2), Meron D(1), Munafo M.R. (3), Baldwin D.S.(1), Garner M(1,2). (1) Medicine, Univ of Southampton (2) Psychology, Univ of Southampton (3) Experimental Psychology, Univ of Southampton

Inhalation of 7.5% carbon dioxide increases anxiety and autonomic arousal and provides a novel experimental model of generalized anxiety with which to evaluate future pharmacological and psychological treatments for anxiety. To date several pharmacological drugs including benzodiazepines, SSRIs and SNRIs have been evaluated using the 7.5% CO2 model, however the model has yet to be used to evaluate psychological interventions. Mindfulness is a form of mental training/ meditation that in part targets dysfunctional attention mechanisms implicated in emotion dysregulation and the aetiology of mood and anxiety disorders. We compared the effect of two components of mindfulness-based attention training (open monitoring and focused attention) against general relaxation on subjective and autonomic response to 7.5% CO2 challenge in healthy volunteers. 57 healthy screened young adults were randomized to complete ten minutes of focused attention training (n=24), open monitoring (n=23) or a relaxation control group (n=10). Practice was guided by recordings from a consultant psychiatrist (DM) with expertise in mindfulness based-interventions. Practice was completed immediately before inhaling 7.5% CO2 and air. Measures of state anxiety, negative affect, blood pressure and heart rate were taken at baseline and immediately following each 20minute inhalation period. Groups did not differ in pre-test self-report trait anxiety, anxiety sensitivity, attention control or dispositional mindfulness, nor baseline state anxiety, blood pressure or heart rate (F’s < 1.6, p’s > .20). The effect of meditation practice vs. control relaxation on subjective and autonomic response to CO2 (compared to air) was examined using mixed design analysis of variance ANOVA with group (OM, FA, control) and inhalation condition (CO2 vs. air) as independent variables. All three groups experienced increased state anxiety and negative affect following inhalation of CO2 compared to air (p’s, < .01), however the magnitude of CO2-induced anxiety and negative affect was signifi cantly and similarly reduced in OM and FA attention training groups compared to the relaxation control group (p’s < .05). CO2-challenge signifi cantly increased blood pressure and heart rate to a similar degree in all groups. Evidence that open-monitoring and focused attention training attenuates subjective anxiety during 7.5% CO2 challenge in the absence of reduced autonomic arousal is consistent with suggestions that attention training may exert clinical effects through top-down mechanisms that support emotion regulation. Our fi ndings complement those from pharmacological treatment studies to support the further use of CO2 challenge to evaluate future psychological and pharmacological treatments for anxiety.

MA05

DEPLETING BRAIN SEROTONIN ENHANCES CARDIOVASCULAR RESPONSES TO STRESS IN RECOVERED PATIENTS ACROSS FIVE ANXIETY DISORDERS. Hudaib AR, School of Psychiatry & Clinical Neurosci, The Univ of Western Australia, Level 1, D Block QE II Medical Centre Nedlands, Perth AUSTRALIA, 6009, [email protected] Hood SD (1,2), Hince DA (1,2), Davies SJC (1), Argyropoulos SV (1), Corchs F (3), Hudaib AR (2), Vellianitis A (2), Tannenbaum J (2), Robinson H (2), Christmas D (1,2), Bell C (1,4), Potokar J (1), Nutt DJ (5). 1 Psychopharmacology Unit, Univ of Bristol, Whitson Street, Bristol BS1 8NY, UK. 2 School of Psychiatry & Clinical Neurosciences (M521), Univ of Western Australia, QEII Medical Centre, PERTH 6009, Australia. 3Anxiety Disorders Unit, Dept and Inst of Psychiatry, School of Medicine, Univ of São Paulo, Brazil, 4 Dept of Psychological Medicine, Christchurch School of Medicine and Health Science, Univ of Otago,PO Box 4345,Christchurch,New Zealand 5 Division of Neurosciences and Mental Health, Imperial College, London UK.

INTRODUCTION Serotonin promoting agents, especially SSRI antidepressants, may improve outcome of some cardiovascular disorders such as ischaemic heart disease, however it is not known if serotonin has direct cardioprotective effects. Previous research has shown that serotonin manipulation through acute tryptophan depletion (aTD) signifi cantly increased the cardiovascular and psychological response to a stress challenge in SSRI and CBT treated patients with anxiety disorders. METHOD 59 clinically-remitted subjects formed the basis of 6 study groups (SSRI-remitted panic disorder, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress disorder, generalised anxiety disorder, & CBT-remitted panic disorder) studied under a standard aTD vs control, double-blind procedure. Measurement of systolic and diastolic blood pressure and heart rate were undertaken at various time points during the study days. Paired sample t-tests were used to compare the cardiovascular response to stress challenge under conditions of acute tryptophan depletion (aTD) and non-depletion (nD). RESULTS Signifi cant reductions of tryptophan ranging from 66-92% was reported throughout. In the pooled analysis, sBP [P = 0.005, diff = 6.7mmHg, 95% confi dence interval (CI) = 2.1-11.2 mmHg] and dBP [P = 0.019, diff = 5.7mmHg, 95% CI = -0.96-10.4 mmHg] were signifi cantly greater on aTD days compared with nD days. In contrast, HR was signifi cantly reduced [P = 0.028, diff = -4.5mmHg, 95% CI = -8.5 – -.51mmHg]. ANOVA revealed that dBP was signifi cantly different in the GAD group compared to the rest of the anxiety disorders, [F (1,56) = 6.0, P = 0.018] and sBP was trending to signifi cance [F (1,56) = 3.9, P=0.052].The exclusion of the GAD data from the analysis made the results for sBP and dBP more signifi cant [P = 0.001, diff 8.9mmHg, 95% CI = 3.8-13.9 mmHg], [P = 0.002, diff = 8.6mmHg, 95% CI = 3.4-13.8mmHg, respectively]. However, the decrease in HR was made less signifi cant [P = 0.038, diff = -4.7mmHg, 95% CI = -9.0 – -0.26mmHg]. CONCLUSIONS In our pooled analysis of patients with treated anxiety disorders, depletion of brain serotonin caused a statistically signifi cant increase in sBP & dBP, and a decreased HR. The difference in sBP & dBP was made more signifi cant, but became less signifi cant for HR, when GAD was excluded from the analysis. Our data suggest serotonin is important in the regulation of the cardiovascular human stress response, at least in patients with treated anxiety disorders. ABSTRACTS A15

MA06

AN INVESTIGATION OF ATTENTION PROCESS IN CHRONIC FATIGUE SYNDROME: HEALTH-THREAT RELATED ATTENTIONAL BIAS AND THE ROLE OF ATTENTIONAL CONTROL Hou R, Dept of Psychiatry, Clinical and Experimental Sciences, Faculty of Medicine, Univ of Southampton, Academic Centre, College Keep 4-12 Terminus Terrace, Southampton , SO14 3DT, [email protected] Hou R(1), Moss-Morris R(2), Risdale A(3), Jeevaratnam P(1), Mogg K(3), Bradley B(3), Peveler R(1) (1) Clinical and Experimental Sciences, Faculty of Medicine, Univ of Southampton, Southampton, UK (2) Psychology Dept, Inst of Psychiatry, King’s College London, London, UK (3) School of Psychology, Univ of Southampton, Southampton, UK

Background: Attentional bias is an important psychological mechanism that has been extensively explored within literature for anxiety and more recently for chronic pain. Cognitive behavioural models of chronic fatigue syndrome (CFS) and chronic pain suggest an overlap in the mechanisms of these two conditions. The current study investigated attentional bias towards health-threat stimuli in individuals with CFS and in healthy controls, and also examined whether individuals with CFS have impaired executive attention, and whether this was related to attentional bias. Methods: 27 participant with CFS and 35 healthy controls completed a Visual Probe Task measuring attentional bias towards health-threat stimuli, and an Attention Network Test measuring alerting, orienting and executive attention. Participants also completed a series of standard self-report measures. Results: There was a signifi cant difference on overall mean RT [t(25) = 7.27, p < 0.001], with the CFS group displaying a signifi cantly slower mean reaction time of 960ms compared to 577ms in the control group. In addition, the CFS group also showed a trend of greater attentional bias towards threat- words than pictures. Results of three measures of the ANT indicate that there was no signifi cant difference between two groups on either alerting scores [t(25) = -1.54, p = 0.13]or orienting scores [t(25) = 0.20, p = 0.85]. However, the CFS group had signifi cantly higher confl ict scores than the control group [t(30), = 2.79, p = 0.01], indicating that the CFS group have impaired executive attention A 3 (group) x 2 (stimulus type) x 2 (exposure) mixed design ANOVA was used to investigate the relationship further, with three levels of group: CFS with good executive attention; CFS with poor executive attention; and controls. This demonstrated a signifi cant main effect of stimulus type [F(1,58) = 5.00, p = 0.03], and, more importantly, the interaction between stimulus type x group was also signifi cant [F(2,58) = 8.15, p = 0.001]. Post-hoc analyses indicated that CFS individuals with poor executive attention showed a threat-word bias when compared to controls and CFS individuals with good executive attention (p < 0.05). Conclusions: This was the fi rst study to investigate attention processes using a combined experimental paradigm and report an interesting relationship between attentional bias and executive attention in CFS. The study demonstrated that attentional biases in individuals with CFS are dependent on their capacity to voluntarily control their attention, which suggests that adding attentional control strategies to current intervention models may be benefi cial for CFS. Key words: chronic fatigue syndrome, attentional bias, executive control, the Visual Probe Task, Attention Network Test Sources of fi nancial sponsorship: The project was funded by internal funding from both the schools of medicine and psychology at the University of Southampton.

MA07

PROBIOTICS AND THE BRAIN: EFFECTS ON ANXIETY AND REVERSAL LEARNING. O’Hagan CM, School of Psychology, Cardiff Univ, 70 Park Place, Cardiff CF10 3AT [email protected] Lilburn A (1), Good MA (1) (1) Cardiff Univ, School of Psychology, 70 Park Place, Cardiff, CF10 3AT

The prevalence of probiotic administration in the treatment of various gastrointestinal disorders has increased in recent years. The effects beyond the intestinal tract were examined in a study by Desbonnet et al (2009, Journal of Psychiatric Research, 43:164-174), results indicated alterations in serotonin metabolism in the frontal cortex and dopamine in the amygdaloid cortex. The aim of the studies presented here were to establish whether these alterations in neurochemical function could be detected at a behavioural level. One group of rats received a chronic dose of Bifi dobacterium infantis and Lactobacillis acidophilus from birth whilst the other group received a standard diet. Two studies were used to examine the emotional and cognitive effects of probiotic administration. The open fi eld test was used to examine the effect of dietary probiotic administration on anxiety levels. On measures of frequency, duration and the total distance travelled in the central portion of the maze the probiotic treated group were signifi cantly lower (p=0.007, p<0.001, p<0.001) with signifi cantly longer durations at the edges and in the corners of the apparatus (p=0.004, p=0.002) as well as moving signifi cantly faster in this portion of the maze and entering the edges more frequently (p=0.004, p=0.044). A watermaze reversal paradigm was used investigate the potential effects of probiotic administration on fl exibility of behaviour which has previously shown to be sensitive to serotonergic manipulation. Results for this indicate that during the latter part of the acquisition phase the probiotic treated group spent signifi cantly more time in the correct quadrant of the watermaze than the control group (p=0.03). During probe trials of the reversal phase the probiotic treated group had a signifi cant session by group interaction in the number of platform crossings compared with controls (p=0.039). These studies demonstrate a signifi cant effect of probiotic administration on emotion with rats showing higher levels of anxious behaviour compared with controls and also a signifi cant effect on acquisition and reversal of reference memory in the watermaze. The effects of probiotic administration on cognition found here have never previously been demonstrated and give a positive indication of a gut-brain interaction with attenuation of neurochemical metabolism by probiotics signifi cantly impacting cognition. Funding: School of Psychology, Obsidian Research A16 ABSTRACTS

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ANTIDEPRESSANT EFFECTS OF NOVEL KAPPA-OPIOID RECEPTOR ANTAGONISTS IN THE FORCED SWIM TEST Bailey SJ, Pharmacy and Pharmacology, Univ of Bath, Claverton Down Bath, BA2 7AY [email protected] Casal-Dominguez, JJ Husbands, SM - Address as presenting author

Introduction: Activation of kappa-opioid receptors (KOR) has long been known to produce dysphoric effects (Pfeiffer et al., 1986, Science, 233:774-776) and KOR antagonists have been suggested as potential treatments for mood disorders (Mague et al., 2003. J Pharmacol Exp Ther, 305:323-330). We have reported previously that 5’-(2-Aminomethyl) naltrindole (5-AMN) and 5’-(2-Methylamidino) butyl naltrindole (5-MABN) are potent, long-acting KOR antagonists in vivo using the tail withdrawal assay (Bailey et al., 2010, J Psychopharmacol, 24: A42) and these compounds have anxiolytic effects in the elevated plus maze (Bailey et al., 2011 J Psychopharmacol, 25: A76). Here, we have investigated the effects of 5-AMN and 5-MABN on depression-related behaviours in mice. Methods: CD-1 male mice, 8-9 weeks old (University of Bath) were handled daily for 1 week prior to treatment. Animals were group housed (n=3-4) and randomly assigned to saline control (0.9% w/v saline) or drug-treated groups (n=10 per group). At day 0, mice were injected (10 ml/kg; ip) with 0.9% w/v saline, 5’-AMN (1 mg/kg), 5’-MABN (1 mg/kg and 10 mg/ kg) or norBNI (1 mg/kg and 10 mg/kg). On test days, 6, 13, 20 and 27 days post-injection of KOR antagonist or saline, mice previously injected with KOR antagonists received saline, 30 min prior to behavioural testing. Control groups previously injected (at day 0) with saline were administered fl uoxetine (10 mg/kg) or U50,488 (5mg/ kg) 30 min prior to testing. Behavioural effects were studied in a 6 min forced swim test (FST) session in a beaker of water (25°C). Subsequent video analysis determined the amount of time spent swimming, climbing or immobile in the test. Data were analysed using a repeated measures one-way ANOVA, and Tukey-Kramer post-hoc test (Stat View 5 software). Results: In the FST, there were signifi cant effects of both drug-treatment [F(7, 216)= 15.06, P<0.0001] and time [F(3, 216)=144.70, P<0.0001] on the time spent immobile. Post-hoc analysis revealed that the antidepressant fl uoxetine (10 mg/kg), decreased the time spent immobile whereas the KOR agonist U50,488 (5 mg/kg), signifi cantly increased the time spent immobile on days 6 and 13 of the study (Ps< 0.01). In contrast, the KOR antagonists norBNI, 5’-AMN and 5’-MABN, signifi cantly decreased the time spent immobile in the FST at 6 and 13 d post-injection, compared with saline-controls (all doses, Ps< 0.01). At 20 and 27 d post-injection there were no signifi cant effects on time spent immobile in the FST. Conclusion: 5’-AMN, 5’-MABN and norBNI displayed antidepressant-like effects in the FST. The antidepressant-like effects were long-lasting in agreement with our previous in vivo studies. Supported by the University of Bath, The Royal Society (SJB), and NIDA DA07315 (SMH).

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WISTAR KYOTO RATS HAVE A “DEPRESSIVE-LIKE” PHENOTYPE ACCOMPANIED BY FUNCTIONAL ALTERATIONS OF BRAIN MICROTUBULES AND CHANGES IN MICROTUBULAR PROTEINS IN THE HIPPOCAMPUS Cottin J, Psychopharmacology MAPREG, 80, rue du General Leclerc Le Kremlin-Bicetre Cedex FRANCE, 94276, [email protected] Leandri J(1), Parésys L(1), Baulieu EE(1), Bianchi M(1) (1)MAPREG, Le Kremlin-Bicêtre, France

Wistar Kyoto (WKY) rats derived from Wistar (WI) rats and display “depressive-like” features (Burke et al., 2010, Neuroscience 171:1300-1313). Changes in microtubular proteins indicative of decreased microtubule dynamics are observed in different experimental models of depression. Here the behavioural phenotypes, brain microtubule polymerization and hippocampal expression of microtubular proteins in WKY were compared to those of WI and Sprague Dawley (SD) rats. Male (8 weeks) WKY, WI and SD rats underwent different behavioural assays. Animals (n=8 per strain) were tested in the open fi eld to detect locomotor activity (LMA; distance travelled in cm) and in the elevated plus maze (EPM) to measure anxiety as open arms (OA) index. Three days after the EPM the whole brains were removed and pooled together for each strain in order to extract microtubules. In vitro brain microtubules polymerization experiments were performed and results expressed as area under the curve. Another cohort of rats (n=6 per strain) performed the forced swimming test (FST) to measure (sec) passive coping (immobility) behaviour. Individual hippocampi were dissected 24h after the FST and expression of microtubule dynamics markers (Tyr/Glu-Tub and Acet-Tub) analysed by Western blot. One-way ANOVA was used to analyse data which are expressed as mean±SEM. LMA was lower (p<0.001) in WKY (954±111) compared to WI (1935±148) and SD (2394±151), and in WI compared to SD (p<0.05). OA-index was reduced in WKY (0.007±0.004) compared to WI (0.090±0.032; p<0.05) and SD (0.184±0.036; p<0.001), and in WI compared to SD (p<0.05). WKY (117±11) had a tendency (p=0.06) to be more immobile in the FST compared to SD (80±10), but no differences were detected against WI (103±17). The ratio of in vitro brain microtubules polymerization of WKY (7385±111) was reduced (P<0.001) compared to WI (8689±97) and SD (8094±57). Analysis of hippocampal Tyr/ Glu-Tub:Acet-Tub ratio was suggestive of decreased microtubule dynamics in WKY (0.23±0.04) compared to both WI (0.74±0.04) and SD (1.01±0.04), the latter were also different from WI (p<0.01). Our results confi rm a “depressive-like” behavioural phenotype in WKI compared to WI and SD. This was accompanied by alterations at different microtubular levels. Thus, microtubule polymerization was altered in the whole brain of WKY rats suggesting changes in microtubule function and composition. Consistently, WKY showed changes in microtubule dynamics markers indicative of decreased dynamics, as observed in other rat models of depression (Bianchi and Baulieu, 2012, PNAS 109:1713-1718). The WKY behavioural and molecular alterations were more evident when compared to SD than WI.

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THE EFFECTS OF CHRONIC FLUOXETINE IN THE RODENT AFFECTIVE TONES DISCRIMINATION TASK Anderson MH, School of Physiology and Pharmacology, Univ of Bristol, Medical Sciences Bldg, University Walk , BS8 1TD, [email protected] Robinson ESJ – address as presenting author

Studies have shown that cognitive processes such as attention, memory and judgement are biased by underlying affective state in humans (Leppanen, J. M. (2006). Current Opinion in Psychiatry, 19, 34-39). Similar cognitive affective biases have been reported in a number of species including rats (Harding et al., (2004), Nature, 427, 312; Enkel, et al., (2009). Neuropsychopharmacology, 35, 1008-1015). This study aimed to investigate the effects of chronic fl uoxetine in a rodent cognitive bias task. We evaluated the effects of treatment on anticipation of positive outcomes and included an estimate of judgment bias calculated from the proportion of reward versus avoidance responses made during ambiguous tone presentation. Twenty male Lister-Hooded rats were trained to lever press to two distinct, randomly presented audio cues (2KHz and 8KHz, counterbalanced, 35 trials/tone) for the acquisition of food reward (45mg food pellet) or avoidance of punishment (1 second footshock, 0.23-0.39mA). Once animals had reached a stable level of discrimination accuracy (>60%), animals were used for pharmacological investigations. In this chronic study, animals were dosed daily with saline or fl uoxetine (1mg/kg i.p) for three weeks followed by one week washout and were tested twice/week using an ambiguous midpoint tone (30 trials). Response choice, omissions and response latencies were recorded. A bias score was calculated as the proportion of reward versus avoidance responses to the midpoint tone. No differences were observed between treatment groups prior to treatment however a signifi cant negative bias was observed for both groups under baseline conditions. This negative bias tended to be attenuated by fl uoxetine after one week and the effect persisted for the duration of treatment and after cessation. No effects of treatment on accuracy or omissions were found (p > 0.05) and response latencies for reference or ambiguous tones were not signifi cantly different. Control animals maintained a relatively stable level of performance across the task. A negative judgement bias was seen in rats with animals making relatively more negative interpretation to ambiguous cues, mirroring our previous fi ndings in humans (Anderson, et al., (2011). Cogn Affect Behav Neurosci., (in press)). Fluoxetine was apparently able to attenuate this effect after one week of chronic dosing with effects persisting after discontinuation; although this was not signifi cant. These results suggest that the affective tones discrimination task may be sensitive to changes in affective state although replication with increased statistical power is necessary. ABSTRACTS A17

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THE SEX-DIFFERENTIATED BEHAVIORAL RESPONSE IN THE FORCED SWIM STRESS FOLLOWING SERTRALINE TREATMENT Kokras N, Dept of Pharmacology, Medical School, Univ of Athens, 75 Mikras Asias st, Athens, Greece 1152, [email protected] Dalla C(1), Kafetzopoulos V(1), Mikail HG(1), Papadopoulou-Daifoti Z(1) (1) Dept of Pharmacology, Medical School, Univ of Athens, Athens, Greece

Recent evidence suggests that response to antidepressant treatments may be sex-differentiated and the female hormonal milieu may be a key modulating factor. Animal models, and in particular the Forced Swim Test (FST), are widely used to screen for antidepressant potential of established and candidate antidepressants. Although the FST is well-validated in male animals, there is still controversy regarding the female performance and the role of estrous cycle in modulating the antidepressant behavioral response. Therefore, in the present study, we investigated the hypothesized sex-dependent effects of antidepressant treatment in the FST, also controlling for the modulating role of the female estrous cycle. Adult male and female Wistar rats were subjected to a 15min FST pretest session and then treated at 0, 19 and 23 hours post-FST with three injections of vehicle or sertraline. Rats receiving sertraline were further divided into those receiving a lower dose of 10mg/kg and a higher 40mg/kg dose. Twenty-four hours after the pretest session, they had a second 5min FST test session. Immobility duration was recorded as an index of passive behavior. Furthermore, swimming and climbing behaviors were recorded as indices of active serotonergic and noradrenenergic behavioral responses, respectively. Meanwhile, the estrous phase of female rats was monitored through vaginal smears. Results were analyzed using a factorial treatment x sex and treatment x estrous cycle MANOVA model. Regarding immobility duration, analysis indicated only a signifi cant treatment effect (p<0.001) given that both sertraline doses effectively reduced immobility duration in both sexes. However, signifi cant sex x treatment interactions emerged in swimming and climbing behavioral responses (p=0.014, p=0.005 respectively). In males, sertraline dose-dependently increased swimming behavior. In contrast, in females the antidepressant-induced increased swimming response showed no dose- dependent differentiation. Instead, the higher sertraline 40mg/kg dose increased climbing behavior. Furthermore, the factorial analysis examining the effect of estrous cycle in females did not show a signifi cant interaction with sertraline treatment but only indicated a signifi cant main effect of estrous cycle in baseline swimming duration (p=0.014). In conclusion, present results indicate that whereas antidepressant treatment reduces immobility in the FST in both sexes, signifi cant sex-differences may be seen in the organization of the antidepressant-mediated organization of the FST active behavioral responses. However, the dose-dependent differentiation between males and females in swimming and climbing responses suggests that females may be more susceptible to a modulation of the catecholaminergic neurotransmission following treatment with higher doses of selective serotonin re-uptake inhibitors. Sources of Financial Sponsorship: None

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SHORT-TERM ANTIDEPRESSANT ADMINISTRATION MODULATES CARDIOVASCULAR RESPONSE DURING EMOTION REGULATION IN SUBJECTS AT RISK FOR PSYCHOPATHOLOGY Di Simplicio M, Psychiatry, Univ of Oxford, Neurosciences Bldg, Warneford Hospital OX3 7JX [email protected] Western D(1), Hanson B (1), Taggart P(2), Harmer CJ (3) (1)Dept Mechanical Engineering, University College London, London, UK (2) Neurocardiology Research Unit,

University College London, London, UK (3)Univ Dept of Psychiatry, Warneford Hospital, Oxford, UK Introduction: Recent studies suggest that alterations in the cardiovascular response to emotional challenges may mediate the relationship between higher risk of cardiovascular disease and emotional disorders (Critchley HD, et al., 2005, Brain 128, 75-85). It is well-established that serotonin reuptake inhibitors (SSRIs) exert changes in basic tasks of emotion processing early on in treatment, while early effects on more cognitively engaging tasks have not been tested yet (Harmer, CJ, 2008. Neuropharmacology 55, 1023-8). The impact of SSRIs on cardiovascular reactivity also remains unclear. The aim of our study was to compare the effect of short term repeated SSRI administration and placebo on cardiovascular reactivity during an emotion regulation task in subjects with high neuroticism scores, who we have previously shown to present an altered High Frequency Heart Rate Variability (HF-HRV) response to emotionally salient stimuli (Di Simplicio M, et al., 2011, Psychol Med Nov 9:1-9). Methods: In a double-blind randomised study, 32 subjects (18 male, 16 on citalopram) with high neuroticism scores (>16) on the Eysenck personality Questionnaire received 7 days of citalopram or placebo and then performed an emotion regulation task (Phan, K, et al., 2005, Biological Psych 57(3), 210-9), involving either passive viewing or down-regulation of affect elicited by negative pictures, while an ECG was recorded. Results: Signifi cant interactions were found between treatment group and emotion regulation task on HF-HRV measures (F(1,28)=4.484, p=.043) and HR acceleration response (F(1,28)=6.367, p=.018), in the absence of any mood or anxiety changes. Citalopram treated subjects failed to increase HF-HRV while down-regulating negative emotion elicited by unpleasant pictures; however citalopram also decreased HR acceleration during passive viewing of the same pictures compared to placebo. Conclusions: This is the fi rst study to show that SSRI short- term administration can modulate cardiovascular reactivity during an emotion regulation task in subjects at risk for psychopathology. Further investigations are needed to evaluate whether these complex modifi cations of HRV and HR phasic responses during emotion regulation may have an additive favourable or detrimental outcome on the autonomic nervous system adaptive capacity to environmental changes and its impact on both treatment of emotional disorders and risk of cardiovascular disease.

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FAMILIAL DEPRESSION: FINDING BIOMARKERS OF VULNERABILITY McCabe C, Psychiatry, Oxford Univ, Neuroscience Bldg, Warneford Hospital, OX37JX [email protected] Woffi ndale C, Harmer CJ, Cowen, PJ. Psychiatry Dept, Neuroscience Bldg, Warneford Hospital, Oxford Univ OX37JX

Abnormalities in the neural representation of rewarding and aversive stimuli have been well described in patients with acute depression and we previously found abnormal neural responses to rewarding and aversive sight and taste stimuli in recovered depressed patients (McCabe et al., 2009 Psychopharmacology (Berl), 205(4):667-77). The aim of the present study was to determine whether similar abnormalities might be present in young people at increased familial risk of depression but with no personal history of mood disorder. We therefore used functional magnetic resonance imaging (fMRI) to examine the neural responses to pleasant and aversive sights and tastes in 25 young people (aged 16-21 years) with a biological parent with depression and 25 age and gender matched controls. Using SPM8 our between group analyses report small volume corrections for brain regions in which we had an a priori hypothesis based on our previous studies in young people at increased familial risk and healthy controls and recovered depressed patients with the current task, as follows; ventral striatum anterior cingulate cortex, orbitofrontal cortex, lateral orbitofrontal cortex and caudate. We found that relative to the controls, participants with a parental history of depression showed diminished responses in the orbitofrontal cortex (p=0.01, z=2.94) to rewarding stimuli while activations to aversive stimuli (p=0.005, z=3.29) were increased in the lateral orbitofrontal cortex and insula. In anterior cingulate cortex the at- risk group showed blunted neural responses to both rewarding (p=0.02, z=2.7) and aversive stimuli (p=0.03, z=2.58). Our fi ndings suggest that young people at increased familial risk of depression have altered neural representation of reward and punishment, particularly in cortical regions linked to the use of positive and negative feedback to guide adaptive behaviour. Funded by Medical Research Council Grant no (HQRORVO). A18 ABSTRACTS

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DOES MATERNAL HISTORY OF CHILDHOOD ABUSE AFFECT MENTAL HEALTH DURING PREGNANCY? Fantini E, Psychological Medicine, Inst of Psychiatry, King’s College London , Inst of Psychiatry, PO Box 71, 16 de Crespigny Park, London SE5 8AF enrica.fantini@ kcl.ac.uk Conroy S(1), Pawlby SJ(1), Osborne SA(1), Pariante CM(1) (1) Inst of Psychiatry, de Crespigny Park, London SE5 8AF

Aims: Previous studies have found that childhood adversities predict depression in adulthood, particularly in vulnerable periods, such as during pregnancy. We aimed to test this in a sample of pregnant women with and without depression. Method: The study includes a sample of 58 pregnant women (26 with a diagnosis of depression, 14 “at risk” women with a history of depression but not depressed in pregnancy, and 17 healthy controls. Assessments made at 25 weeks of pregnancy included the Childhood Experience of Care and Abuse Questionnaire (CECA-Q; Bifulco et al, 2005; British Journal of Clinical Psychology, 44, 1-20), questionnaires about recent life events and intrusive life events and SCID I diagnoses. Results: Women with depression in pregnancy had experienced signifi cantly more adverse childhood and lifetime experiences compared with at risk women and healthy controls. They were more likely to have lost a parent before age 17 through separation or death (X2=11.35, p<0.05) and to have been sexually abused before age 17 (X2=6.53, p<0.05). They had had experienced a higher number of different family arrangements before age 17 (X2= 10.33; p<0.05), and a higher total of intrusive events in their lifetime (one-way Anova: F = 10.10; p<0.001). However, there were no diagnostic group differences in the number of recent life events experienced. Conclusions: This study replicates previous fi ndings that physical and sexual abuse histories are positively associated with pre-natal depression (Rich-Edwards et al., 2010; International Journal of Epidemiology, 40:175-384) and that women with pre-natal depression are signifi cantly more likely to have experienced bereavement of either parent in early life. Financial support: £500 departmental support

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VERBAL MEMORY IN POSTPARTUM PSYCHOSIS Hazelgrove KM, Dept of Psychosis Studies, Inst of Psychiatry, De Crespigny Park London SE5 8AF [email protected] Pauls AM(1,2), Mehta MA(2), Pawlby S(3), Ciufolini S(1), Pariante CM(3), Morgan K(4), Dazzan P(1) (1) Dept of Psychosis Studies, Inst of Psychiatry, De Crespigny Park, London SE5 8AF; (2) Dept of Neuroimaging, Inst of Psychiatry, De Crespigny Park, London SE5 8AF; (3) Dept of Psychological Med, Inst of Psychiatry, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU; (4) Dept of Psychology, Univ of Westminster, 309 Regent Street, London W1B 2UW.

Introduction Verbal memory has been found to be impaired in people at risk of psychoses unrelated to childbirth (Valli et al, 2012. Current Pharmaceutical Design; 18: 1-16). However, little research has been done investigating verbal memory in women at risk of postpartum psychosis (women with bipolar or schizoaffective disorder or a personal or family history of postpartum psychosis; Spinelli, 2009. American Journal of Psychiatry; 166:4: 405-408). This study investigates verbal memory in women at risk of postpartum psychosis compared to a healthy control group. Method 35 women were assessed using a verbal memory task consisting of an encoding and a retrieval stage. Women were either at risk due to a diagnosis of bipolar (N=10), or schizoaffective disorder (N=2) or a family history (N=1) or previous episode of postpartum psychosis (N=7), and 15 healthy controls. Participants were fi rst presented with a list of 70 words and asked to identify whether the words were ‘man-made’ or ‘natural’ objects. After one and half hours participants had to decide, from a second list containing the 70 old and 35 new distractor words, whether a word was previously presented or not. Results There was no signifi cant group difference in the percentage of correctly encoded words (Mean=.92, SD=.06, Mean=.89, SD.06 for controls and at-risk, respectively) or incorrectly encoded words (Mean=.06, SD=.05, Mean=.07, SD=.05 for controls and at-risk, respectively). There was a signifi cant difference between groups in the d prime, indicating participants’ sensitivity, with the healthy control group having a higher hit rate (percentage of words correctly identifi ed as old when previously presented) and a lower false alarm rate (percentage of words incorrectly identifi ed as old when not previously presented) than the at-risk group (Mean=2.73, SD=.67, Mean=1.75, SD=.55, respectively; F1,33=8.34, p=.007). Conclusion Our results suggest that, women at risk of postpartum psychosis have a poorer verbal memory compared to healthy controls. This is in line with previous fi ndings (Valli et al, 2012. Current Pharmaceutical Design; 18: 1-16), indicating that women at risk of postpartum psychosis share some cognitive impairments with other psychoses unrelated to childbirth. The study was funded by The Psychiatry Research Trust and The National Alliance for Research on Schizophrenia and Depression.

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MOTHER-INFANT INTERACTION IN MBU PATIENTS: BEFORE AND AFTER TREATMENT Kenny MA, Perinatal Psychiatry, Inst of Psychiatry, De Crespigny Park, London SE58AF [email protected] Conroy S(1), Pariante C(2), Seneviratne T(1), Pawlby S(1) (1) IoP, KCL, De Crespigny Park, London, SE58AF (2) Room 2-055, The James Black Centre 125 Coldharbour Lane London SE5 9NU

Aim: To compare the mother-infant interaction of in-patients on a Mother & Baby Unit (MBU) on admission and discharge with that of a community well group and mothers with depression and personality disorder in the community. Introduction: Improvement in the mother-infant relationship is an important marker of the effectiveness of an admission to a psychiatric Mother & Baby Unit. Measures that look at this can be helpful in demonstrating more detailed or specialist outcomes in specifi c patient groups, such as mothers admitted with their babies to a psychiatric MBU. Method: Mother-infant interaction was assessed in 49 MBU inpatients at admission and discharge using the Care Index (Crittenden, 2004 ,Miami, FL, Family Relations Institute.). During MBU admission, mothers took part in video feedback sessions. Their interactions were compared to the interactions of 22 mothers in the community with no mental health diagnoses and 67 community women with a diagnosis of depression and personality disorder. Paired outcomes were generated for MBU mothers and infants and compared with other groups using a one-way ANOVA. Results: On admission, MBU mothers were more unresponsive to their babies than community well mothers and did not differ signifi cantly from community unwell mothers. On discharge, MBU mothers were less unresponsive to their babies than community unwell mothers and did not differ signifi cantly from community well mothers. On admission, MBU babies were less co-operative than the babies of community well mothers and did not differ signifi cantly from babies of community unwell mothers on passivity scores. On discharge, MBU babies were more co-operative and less passive than the babies of community unwell mothers and there were no signifi cant differences between MBU babies and those of community well mothers on co-operative scores. These fi ndings were signifi cant at a p<.05 level. Conclusion: Admission to an MBU and undergoing video feedback intervention is effective in improving mother-infant interaction among mothers with severe mental illness. This supports the importance of early intervention for mothers with mental health problems and their babies. Sources of Financial Support: Psychiatry Research Trust and the Trustees of the South London and Maudsley NHS Trust. ABSTRACTS A19

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TH1/TH17 AND TREG/TEFFECTOR IMBALANCE IN DEPRESSED COPD PATIENTS Rybka J, Dept of Biochemistry, Nicolaus Copernicus Univ in Toruń, L. Rydygier, Poland, Karlowicza 24 St. Bydgoszcz, Poland, 85-092, joanna.rybka@scienceventure. eu Kędziora-Kornatowska K(2), Carvalho LA(3), Cattaneo A (4), Czajkowska-Malinowska M(5), Kupczyk D(1), Pariante C(6), Kędziora J (1). (1)Dept of Biochemistry, Nicolaus Copernicus Univ in Torun, L. Rydygier, Poland (2)Dept and Clinic of Nicolaus Copernicus Univ in Torun, Poland (3) Dept of Epidemiology and Public Health, Univ Coll London, UK (4) IRCCS San Giovanni di Dio, Fatebenefratelli, Brescia, Italy (5) Kujawsko-Pomorskie Pneumonology Centre, Bydgoszcz, Poland (6) Inst of Psychiatry, Kings College London, UK

Introduction: Depression is a highly prevalent comorbidity in patients suffering from chronic obstructive pulmonary disease (COPD). Both, depression and COPD are believed to be associated with infl ammation. The aim of our study was to compare immune functions in individuals with both chronic obstructive pulmonary disease and comorbid recurrent depressive disorder (COPD+rDD) and individuals with either COPD or rDD alone to fi nd out whether depression in COPD patients is associated with any distinctive features of infl ammation. Methods: Blood was collected from 45 patients amongst which 18 suffered from COPD, 18 were depressed and 9 had COPD+rDD. Serum levels of IL-2, IL-6, IL-8, IL-17A, TNF-alpha, INF-gamma and neopterin were measured by means of ELISA. Flow cytometry was used to analyze a balance between CD4+CD25+CD127 low(Tregs) and CD4+CD25-CD127- (Teffectors) subpopulations of T lymphocytes in peripheral blood. Results: Regarding Th1 type cytokines, IL-2 levels were highest in COPD+rDD (3.20 +/-0.389 pg/mL vs. 2.30 +/-0.176 pg/mL in controls), p<0.05. Likewise, concentrations of INFgamma signifi cantly increased in COPD+rDD patients when compared with controls (24.3 +/-1.49 pg/mL and 17.8 +/-0.70 pg/mL, p<0.05, respectively). We observed signifi cantly decreased levels of IL-17 A in depressed patients (rDD) when compared with controls, 4.54 +/-0.670 pg/mL and 8.87 +/-1.182 pg/mL, respectively, p<0.01. IL-6 displayed opposite pattern, with the lowest concentrations seen in controls (34.7 +/-1.36 pg/mL) and signifi cantly increased levels in rDD and COPD groups, 42.2 +/-1.87 pg/mL (p<0.05) and 41.9 +/-1.51 pg/mL (p<0.05), respectively. Also IL-8 concentrations signifi cantly increased in COPD group 4.46 +/-0.141 pg/mL vs 3.71 +/-0.132 pg/mL, p<0.01. We observed differences in the proportions of T cells in all patients with a clear tendency for increased percentage of Tregs and decreased percentage of Teffectors when compared with controls (p<0.05). Signifi cant increase in neopterin levels was observed both in rDD and COPD patients when compared with controls, p<0.001 and p<0.05, respectively. Conclusions: Our data indicate imbalance in proinfl ammatory cytokine status in depressed and COPD patients with a shifted Th1/Th17 cytokine ratios, accompanied by increased ratio of Treg/Teffector cells and increased levels of neopterin suggesting also monocyte activations. Key words: chronic obstructive pulmonary disease (COPD), depression, IL-17A, Tregs, proinfl ammatory cytokines ACKNOWLEDGMENTS: This study was supported by the grant for PhD student Joanna Rybka cofi nanced by European Union from the European Social Fund.

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CANDIDATE GENES EXPRESSION PROFILE ASSOCIATED WITH ANTIDEPRESSANTS RESPONSE: DIFFERENTIATING BETWEEN BASELINE “PREDICTORS” AND LONGITUDINAL TARGETS” Cattaneo A, Dept of Psychological Medicine, Centre for the Cellular Basis of Behaviour, Inst of Psychiatry, Kings College London, 125 Coldharbour Lane London SE5 9NU, [email protected] Uher R(1), Breen G(1), McGuffi n P(1), Gennarelli M(2), Pariante CM(3) (1) MRC SGDP Centre, Inst of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF, UK (2) Genetic Unit Fatebenefratelli, Brescia Pilastroni 5 25125 Brescia Italy (3)Pariante CM Psychiatry & Stress, Psychiatry and Immunology Inst of Psychiatry, Kings College London, Department of Psychological Medicine Room 2-055, The James Black Centre 125 Coldharbour Lane, London SE5 9NU

Despite the increasing variety of antidepressants currently available, only a third of patients respond adequately to treatment, and up to half of them relapse within one year. Unfortunately, we still cannot predict the likely of response of an individual patient to a specifi c drug (Thase 2006). Therefore, there is a pressing need to identify biomarkers that predict future response, as well as biomarkers that are targeted by antidepressants and change longitudinally during antidepressant treatment. To reach this aim, we have analyzed in the leukocytes of controls (n=34) and depressed patients (n=74) prior to and after 8 weeks of antidepressant treatment with escitalopram or nortryptiline (GENDEP study) by Real Time PCR the expression of genes belonging to HPA axis functionality (GR, FKBP5, FKBP4) [1], infl ammation (TNF-α, IL-6, MIF, IL-7, IL-10, IL-1β, IL1-α, IL-4, IL-8) and neuroplasticity (BDNF, VGF, p11) (Chopra et al., 2011). Depressed patients, as compared to controls, had higher FKBP- 5 (p<0.0001) and lower GR mRNA levels (p<0.0001). Moreover, they had higher mRNA levels of IL-1β, ( p<0.0001), IL-6 (p<0.0001), MIF ( p<0.0001), and TNF-α (p<0.0001), and lower levels of IL-4 (p=0.02) and lower mRNA levels of BDNF (p<0.0001), p11 ( p=0.001) and VGF (p<0.0001). We also found that non-responders had higher mRNA levels of IL-1β (p<0.0001), MIF (p<0.0001) and TNF-α (p<0.0001). Indeed the expression levels of MIF, IL-1β and TNF-α at baseline were all strongly and negatively correlated with the treatment outcome (IL-1β, r=-0.56; MIF, r=-0.62; and TNF-α, r=-0.44; all p<0.0001). Antidepressant treatment reduced FKBP5 (p<0.0001) and increased VGF levels ( p<0.0001) only in patients who responded to the treatment, whereas no effect was observed in non-responders (p=0.45 for FKBP-5 and p=0.97 for VGF). IL-6 levels decreased both in responders to escitalopram (p=0.001) and to nortryptiline ( p=0.02). In non-responders group, IL-6 did not change in the non-responders to escitalopram but increased in the non-responders to nortryptiline ( p=0.037). Finally, four genes, namely GR, P11, IL-1β and MIF were regulated by antidepressant treatment, irrespective of the antidepressant used or of treatment response. These results demonstrate that three infl ammation-related genes, IL-1β, MIF and TNF-α, predict lack of response to antidepressants, but successful antidepressant response is not associated with reduction in the levels of these genes; suggesting that persistence of infl ammation is not a factor preventing treatment response, as the levels of these cytokines tend to normalize in both responder and non responders. The project was supported by the Italian Ministry of Health (Ricerca Corrente) and by the European Project GENDEP A20 ABSTRACTS

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THE ROLE OF IMMUNE GENES IN THE ASSOCIATION BETWEEN DEPRESSION AND INFLAMMATION: A REVIEW OF CLINICAL STUDIES Bufalino C, Psychological Medicine, Inst of Psychiatry, King’s College London, KCL CCBB, James Black Centre 125 Coldharbour Lane, London SE5 9NU chiara. [email protected] Hepgul N(1), Aguglia E(2), Pariante CM(1) (1) Inst of Psychiatry, King’s College London (2) Dept of Psychiatry, Univ of Catania, Italy

Depressive disorder is a multi-factorial and complex disease, the aetiology of which is not well understood. However, the role for dysregulation of the immune system in the pathogenesis of depressive disorder is well established. Emerging research suggests biological mechanisms involved in the relationship between infl ammation and depression could be infl uenced by underlying genetic vulnerability. The purpose of this review is to summarize the existing literature on the genetic variants involved in neurobiological pathways associated with both depression and infl ammation. We identifi ed 52 papers via the following sources: PubMed, The Cochrane Library, Scopus Embase, Ovid of Medline, PsycINFO and ISI web of Knowledge. We considered case-control, prospective, twin/family-based association and genome-wide association studies. In addition, we included pharmacogenetic studies to better understand the mechanisms involved in the relationship between infl ammation and depression in relation to antidepressant response. Findings across the literature suggest that functional allelic variants of genes for interleukin-1beta (IL)-1β (e.g. C-511T), tumor necrosis factor-alpha (TNF-α) (e.g. G-308A) and C-reactive protein (CRP) (e.g. rs1205 G/A), as well as genetic variations affecting T-cell function may increase the risk for depression. Moreover, single nucleotide polymorphisms (SNPs) in the IL-1β (Tadic et al. 2008 Neuropsychiatr Dis Treat 4, 269-276), IL-6 and IL-11 genes (Uher et al. 2010 Am J Psychiatry 167, 555-564), may be associated with reduced responsiveness to antidepressant therapy. There is also some evidence indicative of a role of genetic variants of the enzymes, Cyclo-ossigenease2 (COX-2) and Phospholipase2 (PLA2), in the aetiology of depression. Su et al. have shown that polymorphisms in PLA2 BanI and COX2 rs4648308 infl uence the risk of developing IFN-α-induced depression (Su et al. 2010 Biol. Psychiatry 67, 550-557). Finally, SNPs in genes related to the serotonin pathway may play a fundamental role in the shared genetic liability to both depressive symptoms and infl ammation. Our review confi rms that genetic variants infl uence the biological mechanisms by which the innate immune system contributes to the development of depression. However, future studies are needed in order to verify the existing fi ndings, establish the mechanisms underlying confi rmed associations, and identify novel genes within infl ammatory signaling molecules that may be involved in the link between depression and infl ammation. Financial Sponsorship: None

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THE EFFECTS OF PSYCHOSOCIAL STRESS ON CLINICAL OUTCOMES DURING IFN-α TREATMENT Borsini A, Psychological Medicine, Inst of Psychiatry, King’s College London, KCL CCBB, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, alessandra. [email protected] Hepgul N(1), Baraldi S(1), Bufalino C(1), Hotopf M(1), Henderson M(1), Cleare AJ(1), Agarwal K(2), Pariante CM(1) (1) Inst of Psychiatry, King’s College London (2) King’s College Hospital

Combination therapy with interferon-alpha (IFN-α) and ribavirin is the standard treatment for chronic hepatitis C virus (HCV) infection. This treatment unfortunately induces depression and other neuropsychiatric adverse effects in 30-50% of subjects. The exact mechanisms underlying this depression are still not clear. It has been demonstrated that exposure to psychosocial stress plays an important role in depression. We aim to investigate the association between psychosocial stress as measured by brief life events and clinical outcomes such as depression, fatigue, stress and anxiety during IFN-α treatment. We recruited 33 HCV patients undergoing IFN-α therapy (mean±SEM age: 42.2±2.0 years; gender: 69% males). Subjects were assessed at baseline (before treatment) and at weeks 4, 8 and 12 of treatment. Severity of depressive symptoms was assessed using the Inventory of Depressive Symptomatology (IDS). Fatigue was assessed using the Chalder Fatigue Questionnaire, as well as levels of stress using the Perceived Stress Scale (PSS). Anxiety was measured using the Hospital Anxiety & Depression Scale Questionnaire (HADS). In all patients psychosocial stress was assessed at baseline using the Brief Life Events Questionnaire (BLE) and scores were dichotomised to indicate presence or absence of any brief life events in the previous 6 months. Data were analysed using SPSS. IFN-α increases depression, fatigue and stress scores in all patients. Across all time points, depression, fatigue, stress and anxiety scores were signifi cantly higher in patients with a presence of life events (p=0.002, p=0.002, p<0.0001 and p=0.014, respectively). For example, patients with a presence of brief life events have higher depression, fatigue, stress and anxiety scores compared to patients without any life events at baseline (18.4±4.0 vs. 6.9±1.2, 19.5±1.4 vs. 12.7±1.4, 16.7±1.4 vs. 8.8±1.7, 6.2±1.4 vs. 3.6±0.9, respectively) and at treatment week 12 (29.8±2.3 vs. 16.3 ±4.9, 25.9±1.3 vs. 18.5±2.2, 21.7±1.2 vs. 12.1±2.5 and 7.5±0.9 vs. 3.3±1.3, respectively). Our fi ndings show that psychosocial stress may play a role in the pathophysiology of IFN-α-induced symptoms such as depression, fatigue, stress and anxiety. This suggests that individuals who experience psychosocial stress may be more vulnerable to the effects of IFN-α. Future analyses, including biological measures such as pro-infl ammatory markers and cortisol, will allow us to clarify the molecular mechanisms involved in this association. Sources of fi nancial sponsorship: This research was funded by a joint National Institute for Health Research (NIHR), Biomedical Research Council (BRC) strategic project award.

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EFFECT OF INTERFERON-α ON CORTICAL GLUTAMATE AND DEPRESSIVE SYMPTOMATOLOGY IN PATIENTS WITH HEPATITIS C: A PROTON MRS STUDY Godlewska BR, Dept of Psychiatry, Univ of Oxford, PPRU, Neurosciences Oxford, OX3 7JX [email protected] Taylor MJ(1), Near J(1,3), Christmas D(4), Potokar J(4), Collier J(5), Klenerman P(6,7), Barnes (6,7), Cowen PJ(1) (1) Univ Dept Of Psychiatry, Warneford Hospital Oxford, OX3 7JX (2) Dept Of Psychosis Studies, Inst Of Psychiatry, King’s College London SE5 8AF (3) FMRIB Centre, Dept of Clinical Neurology, Univ of Oxford, Oxford, UK (4) Academic Unit of Psychiatry, School of Social and Community Medicine, Univ of Bristol, Bristol, UK. (5) John Radcliffe Hospital, Oxford, UK (6) NIHR Oxford Biomedical Research Centre, Oxford, UK (7) The Peter Medawar Building for Pathogen Research, Univ of Oxford, Oxford, UK

Introduction: Treatment of hepatitis C with interferon-α (IFN-α) is associated with a signifi cant incidence of depressive symptomatology. It has been suggested that the mechanism by which IFN-α might produce depression may involve alterations in the glutamatergic system via alterations in metabolism in serotonergic pathways and INF infl uence on astrocyte function. The aim of the present study was to use MRS, a safe and non-invasive method for measurement of cortical neurochemicals, to assess the effect of IFN-α on cerebral glutamate and glutamine levels in patients receiving IFN-α treatment for hepatitis C and to investigate whether changes in these brain neurochemicals correlate with emergent depressive symptomatology. Methods: Twelve patients with chronic hepatitis C viral infection, scheduled to receive treatment with IFN-α, were scanned twice - before and after 4-6 weeks of treatment - on 3T scanner using SPECIAL sequence; voxel included pregenual anterior cingulate cortex (ACC). Spectra were analysed with LCModel. Measures of mental state obtained at both scans included 16 item Quick Inventory of Depressive Symptomatology (QIDS), Spielberger State Anxiety (STAI) and the Fatigue Severity Scale (FSS). Concentrations were expressed relative to creatine (Cr). Group comparisons were performed using the general linear model (PAWS Statistics). Results: IFN treatment was associated with a statistically signifi cant increase in depression symptoms (p=.01) but not in anxiety or fatigue ratings (p>.15). Treatment was associated with a signifi cant increase in glutamine levels (p=.02) and in glutamine: glutamate ratio (p<.01) but not in glutamate levels (p>.7). No signifi cant effect of IFN was observed on other MRS measures (choline, NAA, inositol). The observed change in cortical glutamine concentration correlated with symptom ratings during treatment for depression (QIDS: r .68, p=.02), and anxiety (STAI: r .69, p=.02), but not fatigue (FSS: p>.8). Conclusions: Our fi ndings suggest that 4-6 weeks treatment with IFN-α leads to an increase in glutamine levels in ACC and that this correlates with depression and anxiety scores; these fi ndings support the hypothesis that IFN-α might produce depressive symptoms via alterations in the glutamatergic system. This might be consistent with increased turnover of glutamate because elevated glutamate neurotransmission should result in more glutamate becoming available for astrocytes to convert to glutamine. The pattern of effects seen here differs from those reported in major depression in general where the ratio of glutamine to glutamate is usually decreased. This suggests that the pathophysiology of major depression and IFN-α induced depression in terms of glutamate changes may differ. This study was supported by the Medical Research Council, the Academy of Medical Sciences and Wellcome Trust, and the John Fell Oxford University Press (OUP). ABSTRACTS A21

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T3/T4 AUGMENTATION OF TREATMENT RESISTANT DEPRESSION Adewusi ODT, Psychiatry, Leeds and York Partnerships NHS Foundation Trust, Asket House 1 Asket Place, LS14 1PP, [email protected] Sule A(1) Nandhra H(2) (1)South Essex Partnership Univ NHS Foundation Trust, Wickford, Essex (2)Coventry and Warwickshire Partnership Trust, Leamington Spa

Major depressive disorder is a principal cause of morbidity and mortality. Full symptom remission is the desired outcome for patients suffering from Major Depression. At least 30% of patients with Major Depression fail to respond to fi rst line antidepressant therapy. A further 20% of this index group of patients will fail to respond to at least two adequate antidepressant trials at therapeutic doses. This secondary group of patients are classifi ed as experiencing Treatment Resistant Depression (TRD). These patients experience decreased functioning in social settings and higher suicide risks. They are at least twice as likely to be hospitalized, and on average, incur costs 19 times those of non-treatment-resistant patients. A number of strategies have been directed at managing suboptimal responses to antidepressant pharmacotherapy. One of these strategies involves the augmentation of a standard antidepressants’ effect by adding an agent not generally considered an antidepressant. AIM: To investigate the effectiveness of the addition of Thyroid hormones – Triiodothyronine, Thyroxine – as augmentation agents to standard antidepressants, in the management of depressive symptoms in euthyroid patients with treatment resistant depression (TRD) METHOD: Electronic searches using Medline, PsycINFO, Cochrane and Embase databases were conducted on relevant prospective articles or abstracts published in the English language between 1979 and 2011. We used the Search and MESH terms: Major OR refractory, AND depression, AND tetraiodothyr* OR triodothyro* OR Thyrox*. We contacted experts in the fi eld of pharmacological augmentation in TRD and also contacted pharmaceutical companies in the UK. RESULTS: A total of two hundred and twenty two citations comprising relevant data were retrieved from the electronic and physical searches. The citations were also cross referenced, and duplicates removed. Treatment resistant depression is defi ned as failure to respond to two antidepressant drugs with different mechanisms of action, each used at an adequate dose for an adequate duration (This criteria is believed to be too stringent and some would accommodate antidepressants from within the same class). No RCTs on augmentation studies after failed treatment with two antidepressants from within the same class OR different classes were found. Five RCTs examining T3/T4 augmentation after one failed trial were found, however these did not meet the criteria of two failed treatments. We found fourteen open label trials examining thyroid augmentation after at least one failed treatment and 3 open labelled trials after at least two failed antidepressant treatments. These (open) trials did not fulfi l our criteria, as the study preferentially examined RCTs. However these studies had defi ned Treatment Resistant Depression according to defi nition used by Nierenberg et al (Neirenberg AA. Amsterdam JD. Treatment-resistant depression: defi nition and treatment approaches. Journal of Clinical Psychiatry. 1990; 51 [suppl 6] 39 – 47), and were considered for the purpose of the study. CONCLUSIONS: The different studies had variable remission rates – between 50% and 62% – when patients with recognised Treatment Resistant depression were commenced on T3/T4 augmentation. This was evidenced by a 50% reduction in scores HSRD scores or equivalent. The studies had non-response rates between 29 – 35%. Study results consistently highlighted better effects in females. The literature highlights a likely treatment strategy in treating individuals with TRD. The study samples were fairly limited and randomised controlled studies need to be conducted to support the studies’ fi ndings. Financial Sponsorship: No funding received

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SLEEP IS SIMILAR IN PATIENTS WITH TREATMENT-RESISTANT DEPRESSION AT DIFFERENT STAGES: INFLUENCE OF DIFFERENT ANTIDEPRESSANTS Durant CF, Psychopharmacology Unit, Univ of Bristol, School of Social and Community Medicine First Floor, Room BF1 Oakfi eld House Clifton Bristol BS8 2BN [email protected] Malizia AL (1), Glue P (3), Nutt DJ (2), Wilson SJ (1) (1) Psychopharmacology Unit, Univ of Bristol, UK (2) Neuropsychopharmacology Unit, Imperial College London, UK (3) Dept of Psychiatry, Univ of Otago, NZ

Many depressed patients do not respond to the standard BNF dose of the fi rst antidepressant tried. They may then progress through a hierarchy of interventions such as increasing dose, switching antidepressants, adding augmenters, ECT (see Malizia & Bridges 1992) etc. We have recently studied sleep in 2 small groups at the more severe end of the treatment-refractory depression spectrum, one about to undergo an intervention targeting the HPA axis, ie high dose bolus infusions of hydrocortisone (HCORT), and one before insertion of intracerebral electrodes for deep brain stimulation (DBS). We compare baseline sleep in these groups with a study using similar methods carried out 21-18 years ago in patients who were about to receive lithium augmentation of their antidepressant. In the HCORT study, there were 10 patients with DSM-IV major depression who had failed at least two treatments in the current episode. In the DBS study, of a total of 8 patients, all had undergone validated psychotherapy, had received an average of 19 psychotropic drugs alone and in combination and had undergone several courses of ECT. In the lithium study, 33 patients with major depressive episode had not responded to treatment for at least 4 weeks at maximum tolerated dose of their fi rst antidepressant. Most were on tricyclic antidepressants, a few took MAOIs and a few were on SSRIs, then a novel treatment. Ages were similar in the 3 groups. Mean depression ratings were similar in the HCORT and lithium groups (Ham-D: H 21.8, L 21.2) and slightly higher in the DBS group (26). There were no signifi cant differences between any sleep parameters in any of the groups. All had long REM latencies (means H 186, D 196, L167), likely to be related to antidepressant-induced REM suppression, and low sleep effi ciency, (H 84%, D 82%, L 79%). Some patients in all the groups were taking additional antipsychotic medication known to increase slow wave sleep (SWS), and time spent in SWS and total sleep time was higher in these patients. There are no previous sleep studies in depressed patients selected on the basis of treatment resistance. Differences in sleep parameters between less severe and more severe patients were not seen, but ongoing chronic sleep disturbance, and effects of REM-suppressing antidepressant drugs and those of sleep-promoting antipsychotics and antidepressants were obvious. Funding provided by North Bristol NHS Trust & The James TUDOR Foundation. A22 ABSTRACTS

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COMPARISON OF DEPRESSION OUTCOMES IN PATIENTS WITH TREATMENT RESISTANT DEPRESSION UNDERGOING DEEP BRAIN STIMULATION. RESULTS FROM THE BRISTOL DBS DEPRESSION (BDBS-D) PILOT STUDY Harrison L, Psychopharmacology Unit, School of Community Based Medicine, Univ of Bristol, Oakfi eld House Clifton, Bristol BS8 2BN [email protected] Malizia AL (1), Harrison L (1), Durant C (1), Wilson S (1), Rich A (1), Nutt D (3), Patel NK (2) (1) Psychopharmacology Unit, Univ of Bristol, UK (2) Dept of Neurosurgery, Frenchay Hospital, Bristol, UK (3) Neuropsychopharmacology Unit, Imperial College, London

Introduction: 30-40% of patients with recurrent or severe major depressive disorder (MDD) are unresponsive to standard treatments. Deep brain stimulation (DBS) is emerging as therapeutic for these patients. Here we report the results of observed and subjective depression scales in 8 patients who took part in a randomised double blind trial of DBS of the subgenual cingulate and the ventral capsule/nucleus accumbens. Methods: Hamilton 17 (HAM-D), Montgomery-Asberg (MADRS) and both S and I CGI were rated. Patients completed Positive and Negative Affect Scale (PANAS) and Profi le of Mood States (POMS-SV). Items from each scale were selected for subsequent analysis of sub-scores. Subjective scales refl ected acute symptom changes while observed ratings encompassed several days. CGI-(S/I)were used to benchmark clinical signifi cance. Results: Three patients remitted, two patients responded and three patients didn’t improve. For the whole group HAMD and MADRS were shown to signifi cantly decrease at all time points (days 60, 120, 180, 240, 300, 360, 420, 480) compared with baseline, this is in spite of nobody achieving remission in the fi rst 240 days. POMS decreased signifi cantly at days 120, 240, 360, 420 and 480.th. PANAS produced nonsensical scores from the outset. Ratings were signifi cantly correlated (HAMd/MADRs r= 0.960, p=<.000; HAMD/POMS r=0.746, p=.02; MADRS/POMS r =0.849, p=.004) .At individual level subjective reports could either lag behind or refl ect a temporary improvement in mood. Sub-scales analysis at 480 days showed signifi cant improvements in anxiety (p=<.001), appetite (p=<.05), depression (p=<.05), sleep (p=<.05) and suicidal ideation/behaviour (p= <.001). The latter decreased from day 60 showing a 45% decline after 480 days, in spite of patients attempting suicide while stimulated in the nucleus accumbens or after stimulator malfunction. Results for individual stimulation locations will also be reported. Conclusion: DBS benefi ts patients with treatment resistant depression. Signifi cant decreases were found at 60 days of treatment in spite of global improvement being poor. DBS also improved somatic, vegetative and psychological symptoms. Reduction of suicidal ideation is critical for those with MDD. POMS-SV behaved well in recording subjective experience while PANAS did not, perhaps because of cultural differences. We are grateful to Friends of Frenchay hospital and Medtronic for donation of equipment in this trial and to the North Bristol NHS Trust and Medtronic for supporting some of the project co-ordination.

MB18

BENEFICIAL EFFECTS OF DBS FOR SEVERE AND CHRONIC TREATMENT RESISTANT DEPRESSION ARE NOT ACHIEVED BY STIMULATING BRODMANN’S AREA 25 OR THE NUCLEUS ACCUMBENS. RESULTS FROM THE BRISTOL DBS FOR DEPRESSION (BDBS-D) PILOT STUDY Malizia AL, Clinical Psychopharmacology and Neurostimulation, Frenchay Hospital, North Bristol NHS Trust, Burden Centre, Bristol BS16 1LE andrea.l.malizia@ bristol.ac.uk Durant C (2), Javed S (1), Rich AS (2), Holmes RB (3), Wilson S (2), Patel NK (1) (1) Neurosurgery Dept, Bristol BS16 1LE (2) Psychopharmacology Unit, Univ of Bristol, BS8 2BN (3) Medical Physics, UHB, Bristol BS2 8LW

Deep brain stimulation (DBS) is emerging as therapeutic in chronic and treatment resistant major depression. The two brain areas that have been postulated to have effects are the white matter lateral to the subgenual cingulate cortex (SGC) including areas corresponding to Brodmann’s areas 24 and 25 (CG24,CG25) and the volume comprising the ventral anterior capsule (VAC) and the nucleus accumbens (NAc). Eight people (two men) with severe and chronic treatment resistant depression were randomised to be stimulated in either SGC or VACNAc fi rst and then if they had not responded stimulation was switched to the alternative positions and eventually to stimulation with all electrodes. Patients and rater were blinded to site of stimulation. The surgical technique uses guide tubes and intraoperative MRI to deliver DBS electrodes to within 1.5 mm from the planned target. Patients were aged 49 ± 8.4 years with a duration illness of 19 ± 14yrs and a length of current episode 11.5 ±10yrs. Five had recurrent depression (mean 3.5 episodes). Two had comorbid Panic Disorder, one Agoraphobia and one OCD. All had anxiety symptoms and had a mean of 6.5 hospital admissions, had taken 18.5 different medicines for depression alone or in combination (excluding benzodiazepines). All had ECT with an average of 4.5 courses and two had VNS. Four required a carer at home. Average MADRS was 40±7 and mean HAM-D 17 was 26±5.8; SCL global severity index, positive symptom distress index and depression subscale were at the 99thcentile. All patients were implanted with four Medtronic 3387 leads and subclavicular programmable neurostimulators were implanted, either non-rechargeable (Kinetra; 7428) or rechargeable (Activa RC; 37601). Stereotactic co-ordinates for the most distal SGC contact were 8 15 -6 mm and 4 -7 mm (x,y,z) for the most distal VACNAc. Three patients remitted (37.5%), two other responded (25%), two had no lasting benefi t and one exited the study early without benefi t. Remission was observed with VAC or CG24 but not with CG25 or NAc stimulation. Remission was achieved where stimulation of other areas had not worked. Response was achieved with contemporaneous stimulation. Most suicide attempts were observed during stimulation of NAc but not SGC. Anxiety decreased as well as depression and subjective ratings showed a time lag compared with observed ones. The Friends of Frenchay hospital supported this study by buying equipment. Medtronic donated some stimulators. Research co-ordination was supported in part by a small grant by NBT and a donation by Medtronic. ABSTRACTS A23

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COMPARISON OF EMOTIONAL PROCESSING IN PATIENTS WITH SEVERE TREATMENT-RESISTANT DEPRESSION (TRD) AND HEALTHY MATCHED CONTROLS: EKMAN FACES AND EMOTIONAL STROOP Diaper A, Psychopharmacology Unit, Univ of Bristol, Social and Community Medicine, Academic Unit of Psychiatry, Oakfi eld House, Oakfi eld Grove, Clifton, Bristol BS8 2BN [email protected] Diaper A(1,2), Durant C(1), Rich AS(2), Patel NK(2), Malizia AL(1). 1) Psychopharmacology Unit, Univ of Bristol, Oakfi eld House, Bristol, BS8 2BN, UK 2) Dept. of Neurosurgery, Frenchay Hospital, Bristol, BS16 1LE, UK.

The ability to identify and respond appropriately to emotions may be impaired in patients with depression (Ridout et al., 2003, Cog Emotion, 17, 101-122), and these patients have shown bias away from positive stimuli (Surguladze et al., 2004, Neuropsych, 18, 212-218). To assess this, two tests of emotional processing were used to compare the perceptions of patients with severe treatment-resistant depression (TRD) with healthy controls without psychiatric disorder, matched for age (±5 years), sex, handedness and educational attainment. All participants gave written informed consent. TRD patients were recruited from a group about to receive Deep Brain Stimulation treatment. Controls were recruited via advertisements and underwent screening to preclude psychiatric disorder. Seven TRD patients (5 females, mean age 48.0, sd 9.06), and 14 matched controls (10 females, mean age 47.0, sd 10.30) were asked to assign happiness, surprise, fear, sadness, disgust or anger to 60 randomised presentations of images of these emotional faces (Ekman & Friesen, 1976, Consulting Psychologists Press). Secondly, they completed an Emotional Stroop task, where participants were asked to name the colours that randomised neutral words (e.g. cherry, desk) and words of social or physical threat (e.g. ashamed, hazard) were written in. Patients found the tasks harder to complete than controls. T-tests showed controls correctly identifi ed anger signifi cantly more often than TRD patients (t(19)=2.43, p=0.025). One-tailed repeated measures ANOVAs revealed TRD patients were signifi cantly slower than controls at the Emotional Stroop task (physical/neutral: F(1,19)=10.93, p=0.002; social/neutral: F(1,19)=13.79, p=0.0005). For all participants, physical (F(1,19)=3.26, p=0.044) and social (F(1,19)=10.24, p=0.003) threat words took longer to react to than neutral words. There was a signifi cant interaction (F(1,19)=3.19, p=0.045) whereby TRD patients took longer over social threat words vs. neutral compared with controls. This was of a similar magnitude to the effect shown in other depressed populations (Klieger & Cordner, 1990, Pers Individ Dif, 11, 19-27). The expected result of bias towards sad faces was not found. Noticeably, the TRD patients were worse at recognising sadness and better at recognising happiness than other major depression groups (Mandal & Bhattacharya, 1985, Percept Mot Skills, 61, 13-14). This may be attributed to a lack of power due to diffi culties in accessing severely TRD patients, or to differences inherent within this population compared with treatable depression patients. However, results show these patients may have impairments when identifying anger and processing social threat words. Thanks to North Bristol NHS Trust for their Small Grant Scheme award.

MB20

RESPONSE TO HYDROCORTISONE INFUSIONS IN PATIENTS WITH TREATMENT RESISTANT MAJOR DEPRESSIVE DISORDER: THE TUDOR STUDY Wood BR, Psychopharmacology Unit, Univ of Bristol, Oakfi eld House, Oakfi eld Grove, Bristol BS8 2BN [email protected] Durant C (1), Scheeres K (1), Sinclair L (1), Rich A (1), Wilson S (1), Malizia AL (1) (1) Psychopharmacology Unit, Univ of Bristol, Oakfi eld House, Oakfi eld Grove, Bristol BS8 2BN

Up to 35% of those suffering from Major Depression don’t respond to currently available pharmacotherapeutic efforts (Trivedi 2006 NEJM 354:1243-1252). Such patients with treatment resistant depression (TRD) are often profoundly disabled and there is a distinct lack of novel therapeutic interventions to offer. Abnormalities in hypothalamic-pituitary-adrenal (HPA) axis regulation are described in TRD. Counter intuitively there is some evidence to suggest that short courses of steroid treatment can result in an improvement in TRD symptoms in those patients undergoing standard pharmacotherapy (Goodwin 1992 J Affect Disord 26:73-83; Arana 1995 Am J Psych 152:265-267; Bouwer 2000 Depress Anxiety 12:44-50). If confi rmed this could offer a simple and inexpensive intervention for a disorder with enormous personal and social costs. We conducted a double blind placebo controlled trial to determine the effects of hydrocortisone (7mg/kg up to a max of 500mg) daily for three consecutive days on the symptoms of MDD in patients with TRD. 10 patients with TRD (current MADRS score of >20, on treatment, failure to respond to at least two types of pharmacological intervention) were recruited. Profi les of Mood States Short Version (POMS-SV) were measured during the administration days (Days 1,2 and 3). Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale 17 (HAM-D) and Hamilton Anxiety Scale (HAM-A) scores were taken at baseline and on Days 4, 8, 15, 22 and 29. Responders were those whose MADRS scores reduced by ≥50%, remitters where MADRS ≤10. No changes were made to patient’s current medication during the study. One patient in the HCORT group and none in the placebo group achieved and maintained remission. Repeated Measures Analysis of Variance (RM-ANOVA) showed a difference in both MADRS and HAM-D change from baseline scores by day 29 between groups. (MADRS p=0.005; HAM-D p=0.02). Over the 3 administration days POMS scores for tension and depression but not anger or vigour decreased signifi cantly for all patients (RM-ANOVA Tension p <0.05; Depression p<0.01). However there was no signifi cant difference for any of the other POMS symptoms or for HAM-A. That one patient in this small sample of treatment resistant patients should show a response which persists at 29 days is suggestive that high dose hydrocortisone could be a potential adjunct treatment in this patient group. This could be mediated through trophic factor changes. This study was supported by a grant from the James Tudor Foundation, WestPoint, 78 Queens Road, Clifton, Bristol, BS8 1QU A24 ABSTRACTS

MC01

EXQUISITE DELINEATION OF HIPPOCAMPI, RETROCOMMISSURAL FORMATION AND INDEUSIUM GRISEUM BY HYDROCORTISONE INFUSION USING ARTERIAL SPIN LABELLING MRI IN MAN McGonigle J, Neuropsychopharmacology Unit, Imperial College London, Burlington Danes Bldg, Hammersmith Hospital Campus 160 Du Cane Road London W12 0NN [email protected] Holmes R(1), Tyacke RJ(1,2), Zelaya F(3), Lightman S(4), Nutt DJ(1,2), Williams SCR(3), Malizia AL(1) 1. Psychopharmacology Unit, Oakfi eld House, Univ of Bristol, Bristol BS8 2BN. 2. Neuropsychopharmacology Unit, Hammersmith Hospital Campus, Imperial College London, London W12 0NN. 3. Centre for Neuroimaging Sciences, Inst of Psychiatry, London SE5 8AF. 4. HWLINE, Univ of Bristol, Bristol BS1 3NY

Corticosteroids have a range of brain effects that are mediated through the glucocorticoid and mineralocorticoid receptors (GR and MR). Endogenous corticosteroids are released from the adrenal cortex and freely cross the blood brain barrier to affect brain function. This study shows the effect of an exogenous bolus of hydrocortisone (cortisol) on regional brain function using the MRI technique of Arterial Spin Labelling (ASL). Through 3D visualisation of the results of this experiment, it is possible to resolve regions most affected by the challenge with a delineation hitherto reserved to artists’ impressions of the limbic system. Thus far this exquisite anatomical delineation in man in vivo has only been possible with receptor binding PET studies (e.g. WAY100635 and the raphe nuclei). Twelve right-handed, healthy, male volunteers (mean age, 34 ± 7 (SD)) were scanned (GE 3T Excite II) on two occasions. At approximately 16:00 hr volunteers were infused with either saline (placebo) or HCORT (7 mg/kg, up to 500 mg). Two pulsed continuous ASL (PCASL) scans were collected, one 15 min before the infusion, and one 95 min after. For all this time, the subjects were lying down in the scanner. These scans provided a resting state regional cerebral blood fl ow (rCBF) map in true physiological units (ml/100g tissue/min). Individual scans from two subjects were lost due to technical problems and the fi nal analysis is based on ten subjects. The resulting images were analysed using in-house code written in Python. Surface rendering was performed using FSLView, while direct volume rendering was performed using MRIcroGL. When restraining visualisation to the two largest contiguous clusters of decreased perfusion (pre minus post-infusion) of more than 4 ml/100g/min at the group mean level, only the hippocampi are observed bilaterally. Performing a less constrained surface rendering at the same threshold, but without the criteria of directly contiguous voxels, the hippocampi are seen to continue their inwards curve in their retrocommissural section, curving around the splenium and forming the indusium griseum that represents the supracallosal hippocampus. ASL robustly measures changes in regional blood fl ow and appears to be a viable method for understanding the role of corticosteroids on brain function. Through visualisation of their effects using modern computer graphics techniques it may be possible to provide a greater elucidation of the nature of these structures in the human brain in vivo and delineate their position if necessary. This work was funded by an unrestricted educational grant from Organon.

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THE CONTRIBUTION OF SUB-CELLULAR BINDING TO DOPAMINE AND OPIOID RECEPTOR PET LIGANDS Quelch DR, Neuropsychopharmacology Unit, Imperial College London, Burlington Danes Bldg, Hammersmith Hospital, Du Cane Raod London W12 0NN d.quelch09@ imperial.ac.uk Parker CA(1), Nutt DJ(1), Tyacke RJ(1) (1) Neuropsychopharmacology Unit, Hammersmith Hospital, Imperial College London W120NN

The binding of various PET tracers have been shown to be sensitive to endogenous release of neurotransmitters. As well as the occupancy model, an internalisation process is thought to contribute to the decrease in binding observed in these studies (Laruelle M.,2000,JCBFM,20(3),423-451). We have previously demonstrated that the three PET ligands, [11C]raclopride, [11C]PhNO and [11C]diprenorphine exhibit a reduced ability to bind in sub-cellular environments compared to those at the cell surface (Quelch D., et al,2011,J.Psychopharm,12(8),A60). Here we have determined the cellular distribution of both the radioligand binding sites and the receptor protein in the absence of a challenge using sub-cellular fractionation combined with radioligand binding and Western blotting. For the dopamine2/3(D2/3) radioligands, [3H]raclopride and [3H]PhNO, pig striatum was used (Yorkshire/Landrace;n=3). For the non-selective μ,δ,ĸ opioid receptor ligand, [3H]diprenorphine, rat whole brain (minus cerebellum) homogenates were used (n=4). Briefl y, tissues were homogenised 10x w/v in sucrose buffer over ice and centrifuged (1000xg,10minutes,4°C). The supernatant was further centrifuged (17000xg,20minutes,4°C) to generate the membrane fraction. The supernatant from this fraction was then centrifuged at (100000xg,60minutes,4°C) to generate the microsomal and cytosolic fractions. For each fraction, total fraction protein content was determined and radioligand binding assays were performed using, [3H]raclopride (20nM), [3H]PhNO (5nM) (specifi c binding determined using 1μM haloperidol) and [3H]diprenorphine (5nM) (specifi c binding defi ned with 10μM naloxone). Western blot analysis (30μg/well) was conducted using polyclonal anti-bodies for D2 and D3 and μ/δ/κ. For both D2/3 radioligands the greatest amount of binding was observed in the membrane fraction ([3H]raclopride=67.90±12.43% and [3H]PhNO=64.24±4.59%). The microsomal fraction contributed ~32% of the total tissue binding with no signifi cant contribution from the cytosolic fraction (~1.7-1.8%). Despite the low cytosolic binding, a large portion of total cell protein was observed in this fraction (49.12±8.21%), in addition intense immunoreactivity was observed here for both D2 and D3. Consistent with these data, the greatest amount of [3H] diprenorphine binding was observed in the membrane fraction (73.71±7.47%) compared to the microsomal (26.24±7.46%) and cytosolic fractions (0.04±0.014%) despite the largest amount of total cell protein and intense μ,δ,ĸ immunoreactivity being present in the cytosolic fraction (67.23±6.61) compared to the membrane (18.17±2.64%) and microsomal (10.86±1.56) fraction. Further studies are currently underway to investigate how the location of receptor protein and binding sites change following pharmacological challenge known to cause neurotransmitter release - a paradigm which has never been examined for the μ,δ,ĸ opioid receptor ligand, [3H]diprenorphine. This work is supported by the BBSRC and GlaxoSmithKline. ABSTRACTS A25

MC03

THE NEURAL MECHANISMS UNDERPINNING DECISION TREE ‘PRUNING’ Lally N, Inst of Cognitive Neuroscience, UCL, Alexandra House, 17 Queen Square London WC1N 3AR [email protected] Huys QJM(123), Eshel N(4), Dayan, P(1), Roiser JP(5) (1) Gatsby Computational Neurosci Unit, Univ College London, UK (2) Wellcome Trust Centre for Neuroimaging, Inst of Neurology, Univ College London, UK (3) Guy’s and St. Thomas’ NHS Foundation Trust, London, UK (4) Harvard Medical School, Harvard Univ, Boston, Massachusetts, USA (5) Inst of Cognitive Neuroscience, Univ College London, UK

Planning is diffi cult, especially when the number of decisions to be evaluated is large and the outcome of preceding decisions affects subsequent ones. We recently demonstrated (Huys et al., 2012, PLOS Computational Biology,8(3):e1002410) that humans employ an instinctual heuristic during planning called ‘pruning’, which drastically reduces the number of options appraised. Specifi cally, we demonstrated that individuals fail to consider branches within a decision tree that contain large negative events, even when this strategy leads to a worse outcome overall. For example, when driving there might exist numerous potential routes: one could choose a faster but more traffi c laden route, suffering the frustration of waiting in a jam; or, baulk at the prospect of congestion, and instead choose a traffi c free, but longer route. On the basis of its well-established role in behavioural inhibition, pruning is hypothesised to be driven by serotonin signalling in structures such as the amygdala and periaqueductal grey (PAG; Dayan and Huys, 2008, PLOS Computational Biology,4(2):e4). Here, we sought to examine the underlying neural correlates of pruning using functional magnetic resonance imaging (fMRI). Forty-one healthy volunteers performed a reinforced sequential planning task during fMRI. Participants were required to plan three to fi ve moves ahead within a maze, with two possible moves available from each position. Each move was associated with a fi xed monetary gain or loss. Trials were classifi ed according to whether the optimal sequence was chosen or not. Suboptimal trials were classifi ed as ‘pruning’ when it was optimal to transition through a large loss, yet subjects avoided these large losses, instead choosing the best alternative sequence. A series of increasingly complex computational models were fi t to the data in an attempt to capture fundamental aspects of behaviour in the task. Mood, personality and intelligence were also measured. On average participants chose the optimal solution 48.76% of the time, though performance worsened with increasing diffi culty (F(1.70,61.28)=132.75, P<0.001). Critically, performance was substantially worse on trials where the optimal decision included a large negative outcome (t(36)=15.2, P<0.001). Computational analysis confi rmed robust evidence for pruning. Trait anxiety positively predicted pruning (r=.41,P=0.017). Pruning was associated with responses in the subgenual anterior cingulate cortex (t(29)=3.63, Psvc=0.023) and PAG (t(29)=3.13, Psvc=0.035). Including each individual’s tendency to prune revealed a strong relationship with response in the amygdala (t(28)=5.09, Psvc=0.001). These results are consistent with the hypothesis that serotonin-driven pruning may play an important role in mood and anxiety disorders.

MC04

HABENULA RESPONSES TO AVERSIVE STIMULI IN HUMANS: A HIGH-RESOLUTION FMRI STUDY Lawson RP, Inst of Cognitive Neuroscience, Univ College London, 17 Queen Square London WC1N 3AR [email protected] Seymour B(1), Loh E(1), Lutti A(1), Thomas DL(2), Dolan RJ(1), Dayan P(3), Weiskopf N(1), & Roiser JP(4) (1) WTCN, FIL, 12 Queen Square, London, WC1N 3BG (2) Dept. Med Phys & Bio Engineering, UCL, London, WC1N 3AR (3) Gatsby Comp. Neuroscience Unit, 17 Queen Square, London, WC1N 3AR (4) UCL Inst of Cog. Neuroscience, 17 Queen Square, London, WC1N 3AR

The habenula comprises a set of small nuclei adjacent to the medial dorsal (MD) nucleus of the thalamus, reciprocally connected with midbrain monoaminergic nuclei. The lateral portion of the habenula (LHb) has been implicated in reinforcement processing (Matsumoto & Hikosaka, 2009, Nat Neuroscience 12(1):77-84) and in the pathophysiology of major depression (Roiser et al, 2009, Biological Psychiatry, 66(5):441-450). In contrast to the reward-related prediction error (PE) signals recorded from midbrain dopamine neurons, the LHb has been shown to respond to aversive stimuli in non-human primates. Previous investigations of habenula function in humans have been limited by the resolution of standard functional magnetic resonance imaging (fMRI) protocols (usually 3mm isotropic), making signal from this structure diffi cult to resolve from the MD thalamus. We report the fi rst high-resolution fMRI study combined with computational modelling to test the hypothesis that the habenula encodes the negative motivational value of stimuli in humans. Healthy volunteers (N=23) performed a Pavlovian conditioning task in which they were passively exposed to abstract fractal images (conditioned stimuli: CS) that led to different reinforcing outcomes (win £1 lose £1; and painful electric shock) in a probabilistic manner. High- resolution T2* echo-planar (1.5mm isotropic) and T1-weighted (0.77mm isotropic) images were obtained using a custom-written sequencees for a Siemens Tim Trio 3-Tesla MRI scanner. Breathing and heart-rate data were collected to correct for pulse-related artefacts. Using a temporal difference learning algorithm (Seymour et al, 2004, Nature, 429:664–667) PEs for wins, losses and shocks were derived for each subject and used as parametric modulators in the fMRI analysis. Conditioning was confi rmed behaviourally both explicitly (preference scores; signifi cant effect of CS type: F(2,44)=149.20, P<0.001; difference between £1 win and electric shock CSs: t(22)=14.43, P<0.001) and implicitly (reaction times; signifi cant effect of CS type: F(2,44)=8.60, P<0.005; difference between £1 win and electric shock CSs: t(22)=3.96, P=0.001). Analysis of responses corresponding to PEs at CS onset in the habenula revealed a signifi cant linear effect of PE type (win, loss, shock) (F(1,22)=6.01, P=0.022). Planned pairwise comparisons revealed that habenula responses to PEs for shocks were signifi cantly greater than to PEs for wins (P=0.022). Strikingly, our behavioural measure of conditioned suppression, the slowing of responses during the presentation of shock-associated stimuli relative to those associated with neutral outcomes, correlated positively with habenula PE responses to shock cues across subjects (r(23)=0.51, P=0.012). These data strongly indicate a role for the habenula in aversive stimulus processing in humans. Financial Support from the Medical Research Council. A26 ABSTRACTS

MC05

DETECTING ENDOGENOUS CHANGES IN SEROTONIN NEUROTRANSMISSION IN HUMANS: A [11C]CUMI-101 AND CITALOPRAM CHALLENGE STUDY Selvaraj S, Inst of Psychiatry, King’s College London, Denmark Hill, London SE5 8AF [email protected] Turkheimer F(2), Faulkner P(4), Mouchlianitis E(1), Roiser JP(4), McGuire P(3), Cowen PJ(5), Howes O (1,3). (1) MRC Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN; (2) Dept of Medicine, Imperial College London, W12 0NN; (3) Inst of Psychiatry, King’s College London SE5 8AF; (4) Inst of Cognitive Neuroscience, Univ College London WC1N 3AR; (5) Dept of Psychiatry, Univ of Oxford, Warneford Hospital OX3 7JX

Introduction: Serotonin (5-HT) neurotransmission is critical for emotion processing in the brain and many antidepressants are thought to primarily work by altering 5-HT levels. However to date, the antidepressants induced changes in 5-HT has not been demonstrated in vivo in Man. The aim of the present study was to assess the sensitivity of a 5-HT1A partial agonist radioligand [11C]CUMI-101 and positron emission tomography (PET) to changes in endogenous 5-HT levels induced by an intravenous challenge with the citalopram, a selective serotonin re-uptake inhibitor (SSRI), in healthy human participants. Methods: We studied 15 healthy participants of which 13 completed PET scanning in conjunction with [11C]CUMI-101 after receiving either an intravenous infusion of citalopram 10mg or placebo in a double-blind, cross- over, randomized design. Estimates of binding potential (BPND) were obtained by calculating total volumes of distribution for presynaptic dorsal raphe nucleus (DRN) and postsynaptic cortical regions (frontal, pareital, temporal, temporal, insula, hippocampus, amygdala and anterior cingulate). Repeated measures analysis of variance (RMANOVA) and paired t-tests were performed to determine if there was a signifi cant treatment effect on BPND in the presynaptic DRN and the postsynaptic regions. Results: RMANOVA revealed a signifi cant treatment effect in postsynaptic regions (F=6.31; df=1, 12; p=0.03). Relative to placebo, citalopram infusion signifi cantly increased [11C]-CUMI-101 binding potential at postsynaptic regions (t= -3.72; df=1; 12; p=0.003) but there was no change in binding at 5-HT1A autoreceptors in the DRN (t= 0.57; df=1, 12; p=0.58). The change in BPND in the DRN was inversely correlated with the change in BPND in parietal cortex (Spearman’s rho -0.55 and p=0.05) but not with that in other cortical regions or the whole post-synaptic ROI considered alone (all p-values>0.3). Conclusion: The observed increase in postsynaptic [11C]CUMI-101 availability identifi ed following acute citalopram administration could be attributable to a decrease in endogenous 5-HT availability in cortical terminal regions. Consistent with preclinical animal studies, in which acute administration of SSRIs decreases DRN cell fi ring through activation of 5-HT1A autoreceptors to reduce serotonin levels in post-synaptic regions (Invernizzi et al 1992. Brain Res; 584(1-2): 322-324; Gartside et al 1995. Br J Pharmacol; 115(6): 1064; Giovacchini et al 2005. Neuroimage; 28(1): 238-248). We conclude that [11C]CUMI-101 may be sensitive to changes in endogenous 5-HT neurotransmission in humans and therefore could be useful as a molecular tool for investigating the 5-HT function in mood disorders. Sources of fi nancial sponsorship: This study was funded by the Medical Research Council, UK. Sudhakar Selvaraj, Federico Turkheimer, Lula Rosso, Elias Mouchlianitis, Paul Faulkner, Jonathan Roiser, Philip McGuire and Oliver Howes report no competing interests. Philip Cowen has been a member of advisory boards of Eli Lilly, Servier and Lundbeck and has been a paid lecturer for Eli Lilly, Servier, Lundbeck and GlaxoSmithKline.

MC06

DONEPEZIL MODIFIES THE DISTRIBUTION OF CHANGES IN REGIONAL CEREBRAL BLOOD FLOW INDUCED BY SCOPOLAMINE ADMINISTRATION IN HEALTHY VOLUNTEERS Doyle OM, Neuroimaging, King’s College London, Centre for Neuroimaging Sciences, P089, De Crespigny Park, London, SE5 8AF [email protected] Zelaya FO(1), O’Daly OG(1), Williams SCR(1), Mehta MA(1). (1) Dept of Neuroimaging, Centre for Neuroimaging Sciences, Inst of Psychiatry, King’s College London, London, UK

Introduction: Scopolamine is a potent antagonist of the muscarinic acetylcholine receptor and is thought to impair memory by blocking cholinergic transmission. Donepezil, an acetylcholinesterase inhibitor, pharmacologically attenuates the effects of scopolamine and can provide some improvement in cognitive impairments in cholinergic animal models of Alzheimer’s disease as well as patients. Here, arterial spin labelling (ASL) is used to measure regional cerebral blood fl ow (rCBF) and test the hypothesis that donepezil will attenuate the central effects of acute cholinergic hypofunction.. Methods: 15 healthy male volunteers participated in a three period latin- square design study, and were administered oral placebo + saline (PLC), placebo + scopolamine (0.2mg; SCOP) or donepezil (5mg p.o.) + scopolamine (DON+SCOP). Whole brain rCBF was measured using pulsed-continuous ASL (pCASL). Data were preprocessed using SPM8 with a T2-weighted image used to determine normalization parameters. We expected that scopolamine would modify rCBF in distributed regions in the brain in line with widespread cholinergic projections. Thus, the rCBF images were analysed using multivariate techniques, in this case, Gaussian process classifi cation. The classifi er was trained on the contrast between PLC and SCOP alone on 14 (N-1) participants and tested on all three conditions (PLC, SCOP, DON+SCOP) for the remaining participants. This enabled quantifi cation of the degree to which the pretreated scans ‘look’ like SCOP. This process was repeated until all participants were used as test subjects. Results: Classifi cation accuracy for the PLC versus SCOP rCBF images was 86.7%. Classifi cation performance was degraded to 60% on testing the pretreated scans; with only 33.3% of the pretreated scans labeled as SCOP by the classifi er. While all regions contributed to the classifi cation accuracy for SCOP the following regions were highly weighted in favour of SCOP: thalamus, cerebellum, insula and parahippocampal gyrus and the following had the most reduced weights for the DON+SCOP versus PLC classifi er: cerebellar and parahippocampal region. Importantly, while these components are prominent, they should be considered within the context of the resultant whole brain pattern. Discussion: Applying multivariate analysis to rCBF data provides a single quantitative marker which indicates the effi cacy for which a pretreatment attenuates a pharmacological challenge. This method can be used to benchmark other novel compounds and investigate dose response relationships. The effects of SCOP include regions previously identifi ed in univariate PET studies, not all of which were attenuated by pretreatment. In particular, at the doses given donepezil did not appear to affect thalamic impairments in blood fl ow. Funded by GSK and in part by NEWMEDs. ABSTRACTS A27

MC07

LATERALISED CORTICAL RESPONSE TO PHARMACOLOGICAL STIMULATION OF GLUCOCORTICOID AND MINERALOCORTICOID RECEPTORS IN MAN Tyacke RJ, Neuropsychopharmacology Unit, Imperial College London, Burlington Danes Bldg, Hammersmith Hospital Campus, 160 Du Cane Road London W12 0NN [email protected] McGonigle J(1,2), Holmes R(1), Zelaya F(3), Lightman S(4), Nutt DJ(1,2), Williams SCR(3) and Malizia AL(1) 1. Psychopharmacology Unit, Oakfi eld House, Univ of Bristol, Bristol BS8 2BN 2. Neuropsychopharmacology Unit, Hammersmith Hospital Campus, Imperial College London, London W12 0NN 3. Centre for Neuroimaging Sciences, Inst of Psychiatry, London SE5 8AF. 4. HWLINE, Univ of Bristol, Bristol BS1 3NY

Corticosteroids have a range of brain effects that are mediated through the glucocorticoid and mineralocorticoid receptors (GR and MR). Endogenous corticosteroids are released from the adrenal cortex and freely cross the blood brain barrier to cause their effect. This study shows the effect of a bolus of hydrocortisone (name for exogenous cortisol) on regional brain function using the MRI technique of Arterial Spin Labelling (ASL). Twelve right-handed, healthy, male volunteers (mean age, 34 ± 7 (SD)) were scanned (GE 3T Excite II) on two occasions. At approximately 16:00 hr volunteers were infused with either saline (placebo) or hydrocortisone (7 mg/ kg, up to 500 mg). Two pulsed continuous ASL (PCASL) scans were collected, one 15 min before the infusion, and one 95 min after. For all this time, the subjects were lying down in the scanner. These provided a resting state regional cerebral blood fl ow (rCBF) map in true physiological units (ml/100 g tissue/min). Individual scans from two subjects were lost due to technical problems and the fi nal analysis is based on ten subjects. The resulting images were analysed using in-house code written in Python, with laterality being examined using a repeated measure GLM analysis in SPSS. There was a highly signifi cant difference between the rCBF for the left and right hemispheres for every ASL acquisition at the group level: hydrocortisone day pre-infusion, hydrocortisone day post-infusion, placebo day pre-infusion, and placebo day post-infusion (p<0.00001). When taking the absolute rCBF values for all the grey matter, for all subjects, on the hydrocortisone day, there is a signifi cant difference in the decrease (post compared with the pre-infusion levels) in perfusion of the left hemisphere of the brain compared with the right (t=3.55, p=0.0046). On the placebo day, for the same test, a signifi cant difference was not found (t=1.14, p=0.28). These results did not change in signifi cance when proportional change rather than difference was calculated. Areas that showed at least twice the lateralisation effect compared with placebo included paralimbic, affective and associative cortex. Limbic and subcortical structures did not show an increase in lateralisation. ASL robustly measures changes in regional blood fl ow and would appear to be a viable method for understanding the role of corticosteroids on brain function. The implication of lateralisation are discussed. This work was funded by an unrestricted educational grant from Organon.

MC08

ABNORMALITIES IN ANATOMICAL CORTICO-SUBCORTICAL CONNECTIVITY ASSOCIATED WITH CHRONIC KETAMINE USE Roberts RE, Centre for Neurosciences Imperial College London, Charing Cross Campus, Imperial College London, London W6 8RF [email protected] Morgan CJA(1), Curran HV(1), Roiser J (2) (1)Clinical Psychopharmacology Unit, Univ College London, Gower St, London WC1E 6BT (2) UCL Inst of Cognitive Neurosci, 17 Queen Square, London, WC1N 3AR

Introduction: Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been found to induce schizophrenia-type symptoms in humans. Acute administration has been associated with impairments of verbal and episodic memory, and impaired error-dependent learning capacity associated with reduced activation of dorsolateral prefrontal cortex (Corlett et al, Arch Gen Psychiatry. 2006; 63:611-621). In naturalistic studies, symptoms of acute administration have also been shown to persist for up to three days. A recent investigation using a murine model suggests that acute administration might also affect connectivity between prefrontal cortex and sub-cortical areas (Dawson N et al, Schizophr Bull. 2011 Nov 22. Epub ahead of print). Although chronic administration of ketamine in animals has been associated with lasting changes to the encoding of sensory stimuli (e.g. Maxwell et al, J Pharmacol Exp Ther 2006; 316: 315–24.), the effect of extended periods of ketamine use on brain structure in humans remains poorly understood. Methods: We acquired diffusion-weighted magnetic resonance imaging data for a group of 16 controls and 16 chronic ketamine users. We measured indices of white matter microstructural integrity and connectivity in the brain, and used probabilistic tractography to explore changes in cortico-subcortical connectivity associated with ketamine use. Results: We found a signifi cant correlation between an index of dissociative experiences (DES score) and the connectivity profi le between caudate nucleus and lateral prefrontal cortex in the right hemisphere (p<0.05), but found no signifi cant differences in the connectivity profi les between the groups. There were also signifi cant differences (p<0.05) between the groups in terms of the longitudinal diffusivity profi le of white matter adjacent to frontal and parietal brain regions. These clusters were located close to the anterior portion of superior longitudinal fasciculus, which contains fi bres that form cortico- subcortical connections, and in the white matter adjacent to intraparietal sulcus and inferior occipito-frontal fasciculus. Conclusion: These fi ndings suggest that chronic ketamine use may be associated with disruption of white matter connections in parietal and prefrontal cortex, and that connectivity to prefrontal regions may modulate the level of dissociative symptoms experienced. Funding: Medical Research Council UK.

MC09

BRAIN GLUTAMATE LEVELS IN CHRONIC KETAMINE USERS – RELEVANCE TO SCHIZOPHRENIA Stone JM, Experimental Medicine, Imperial College London, Burlington Danes Bldg, Hammersmith Hospital, Du Cane Road London W12 0NN james.m.stone@ imperial.ac.uk Pepper F(1,2), Curran V(2), Morgan C(2), Howes O(1) (1) Imperial College London (2) University College London

Introduction: The NMDA receptor dysfunction hypothesis is one of the leading explanatory theories for the neurochemical abnormalities in schizophrenia. Ketamine, a uncompetitve NMDA receptor antagonist induces acute effects that resemble the positive, negative and cognitive symptoms of schizophrenia. It has been suggested that chronic, rather than acute NMDA receptor blockade is more representative of the long-term NMDA receptor dysfunction hypothesised to occur in schizophrenia. Chronic ketamine users represent a population in which NMDA receptor function has been regularly suppressed, and thus, if the NMDA receptor dysfunction hypothesis of schizophrenia is correct, may be expected to have similar neurochemical brain changes as patients with schizophrenia. Patients with schizophrenia have been demonstrated to have elevated glutamate levels in medial prefrontal cortical brain regions, and in the thalamus. In this study, we test the hypothesis that compared with healthy volunteers, chronic ketamine users have increased thalamic and anterior cingulate glutamate+glutamine levels, and that glutamate+glutamine levels correlate with the level of ketamine use. Methods: 20 ketamine users (6F) and 14 controls (6F) (matched for age, sex, IQ and non-ketamine drug use) were recruited by advertising, and gave informed consent to participate in the study. All volunteers completed information about their level of ketamine and other drug use. After this, they underwent proton magnetic resonance spectroscopy (1H-MRS) scanning on a 3 Tesla Philips magnetic resonance imaging system, with data acquired from left thalamus, anterior cingulate (midline), and left hippocampus. Estimations of scaled-to-creatine glutamate, glutamine and NAA levels were generated using LCModel. Results: Ketamine users had elevated creatine-scaled glutamate+glutamine levels in left thalamus (t=2.3, p=0.03). In addition, total lifetime ketamine use (g) was positively correlated with creatine- scaled glutamate+glutamine (p = 0.02) and NAA levels (p = 0.003) in left hippocampus, and was related at trend level to left thalamic glutamate+glutamine scaled to creatine (p=0.09). There was no difference between ketamine users and healthy volunteers in creatine-scaled glutamate, glutamine or NAA levels in hippocampus or in anterior cingulate cortex. Conclusions: This study provides evidence that chronic ketamine users have abnormalities in brain glutamate levels, which resemble some of the changes reported in patients with fi rst episode schizophrenia. This supports the hypothesis that NMDA receptor dysfunction may underlie some of the neurochemical changes in schizophrenia. Drugs targeting glutamatergic neurotransmission may be helpful in the condition, particularly for those patients who fail to respond to domaminergic antipsychotic drugs. Disclosure: This study was funded by the Medical Research Funding A28 ABSTRACTS

MC10 Default mode network in the effects of ∆9-tetrahydrocannabinol (THC) on human executive function Bossong MG, Dept of Psychosis Studies, Inst of Psychiatry, King’s College London, 16 De Crespigny Park, London SE5 8AF [email protected] Jansma JM (1), Van Hell HH (1), Jager G (1,2) Kahn RS (3), Ramsey NF (1) (1) Rudolf Magnus Inst of Neurosci, Dept of Neurology and Neurosurgery, Univ Med Center Utrecht, The Netherlands (2) Div of Human Nutrition, Wageningen Univ, The Netherlands (3) Rudolf Magnus Inst of Neurosci, Dept of Psychiatry, Univ Medical Center Utrecht, The Netherlands

Introduction: Increasing evidence exists for involvement of the endocannabinoid (eCB) system in executive functions which are also affected in psychiatric disorders such as schizophrenia and ADHD (Solowij and Mitchie, 2007, J Psychiatry Neurosci 32, 30-52). In addition, executive function has been associated with both modulation of active brain networks and inhibition of activity in the default mode network (Weissman et al., 2006, Nat Neurosci 9, 971-978). In the present study, we used functional MRI to examine effects of the eCB agonist ∆9-tetrahydrocannabinol (THC) on executive function, focusing on both the associated brain network and the default mode network. Methods: Twenty healthy subjects participated in a double-blind, randomized, placebo-controlled, cross-over pharmacological fMRI study, receiving THC (6 mg) and placebo using a Volcano vaporizer. Executive function was assessed with a continuous performance task with identical pairs (CPT-IP) consisting of a CPT condition and a control condition. In SPM5, effects of THC on brain activity were assessed in two sets of regions showing task-induced deactivation (TID) and task-induced activation (TIA), respectively. Both networks were defi ned based on pooled placebo and THC group activity maps for the CPT minus control contrast (thresholded at t > |4.6|, p<0.0001, clusters ≥10 voxels). Results: Task performance was impaired after THC administration (p<0.05). TID showed a network of four regions, comprising posterior cingulate cortex, left angular gyrus, left inferior temporal gyrus and right cerebellum. TIA yielded a network including bilateral prefrontal cortex, parietal cortex, precentral gyrus, visual cortex and anterior cingulate cortex. THC administration had distinct effects on activity in both networks, as shown by a signifi cant interaction effect between drug and network (p<0.05). TID activity was increased after THC administration (p<0.01), which indicates a THC-induced failure to deactivate the TID network. Less deactivation was signifi cantly correlated with lower performance after THC (p<0.05). TIA activity was not affected by THC administration. Conclusions: THC administration reduced deactivation in a set of brain regions linked to the default mode network, an effect that was correlated with lower performance on an executive function task. This possibly refl ects interference of THC-induced effects with goal-directed behaviour required to maintain good performance levels (Sonuga-Barke and Castellanos, 2007, Neurosci Biobehav Rev 31, 977-986). These fi ndings suggest eCB involvement in both executive function and modulation of default mode activity, as well as a role for both the eCB system and the default mode network in executive function defi cits in psychiatric disorders such as schizophrenia and ADHD. This study is performed within the framework of Top Institute Pharma, project number T5-107.

MC11

ALTERED DEFAULT MODE NETWORK CONNECTIVITY AFTER PSILOCYBIN Carhart-Harris RL, Neuropsychopharmacology Unit, Imperial College London, Burlington Danes Building, 160 du Cane Rd London W12 0NN r.carhart-harris@ imperial.ac.uk Erritzoe DE, Williams TM, Leech R, Feilding A, Wise RG, Nutt DJ Addresses as for submitting author

Introduction: This study used functional magnetic resonance (fMR) to image changes in functional coupling after intravenous infusion of the psychedelic drug psilocybin. Psilocybin is a mixed serotonin receptor agonist that causes profound changes in consciousness. We sought to examine whether these changes could be explained by altered brain network connectivity. Methods: Fifteen healthy volunteers were scanned with BOLD-weighted fMRI during 12 minutes of eyes-closed ‘rest’. Each volunteer has 2 scans on separate occasions. Psilocybin was infused after 6 minutes in one scan and placebo (saline) in the other. Seed-based functional connectivity analyses were used to assess changes in bilateral hippocampal coupling after infusion and independent components analysis (ICA) and seed-based analyses were used to compare between-network coupling after infusion. Results: Signifi cant decreases in functional coupling were found between the hippocampal seed and all of the key nodes of the default mode network (DMN), i.e. the posterior cingulated cortex, medial prefrontal cortex and bilateral inferior parietal lobes (p < 0.05, whole brain cluster-corrected, z = 2.3). Remarkably, these decreases were specifi cally localised to these DMN regions, despite a whole brain analysis. Using mean time series from ICA and seed-derived brain networks we found signifi cant increases in coupling between the DMN and ‘task-positive networks’ (TPNs) after psilocybin (p < 0.01) and these increases correlated with ratings of the intensity of the subjective effects (p < 0.05). Conclusions: The ‘disintegration’ of hippocampal-DMN connectivity after psilocybin was remarkable. The hippocampi are major subcortical nodes of the DMN and it is likely that the cortical regions of the DMN exert top-down control over them. Decreased DMN control of limbic activity may explain labile emotions in the psychedelic state (e.g. euphoria and fear). The signifi cant increases in DMN-TPN coupling after psilocybin are equally intriguing as they imply a ‘blending’ of networks which normally function antagonistically or competitively with each other (Fox et al. 2005, PNAS). Given the strong association between the DMN and the ‘self’ (Qin & Northoff, 2011, Neuroimage), it is tempting to consider whether decreased within-DMN and increased DMN- TPN coupling after psilocybin relate to the much documented ‘ego-dissolving’ or ‘disintegrating’ effects of psychedelic drugs. This research was funded by the Beckley Foundation and the Heffter Research Institute

MC12

NICOTINE ENHANCES PROSPECTIVE MEMORY PERFORMANCE IN APOE E4 CARRIERS: AN FMRI STUDY Evans SL, School of Psychology, Univ of Sussex, Brighton, East Sussex BN1 9QG [email protected] Gray M(2), Dowell NG(3), King SL(1), Tabet N(4), Tofts PS(3), Rusted JM(1) (1)School of Psychology, Univ of Sussex, Brighton, East Sussex BN1 9QG, UK (2)School of Psychology and Psychiatry, Monash Univ, Victoria 3800, Australia (3)Brighton and Sussex Medical School (BSMS), Clinical Imaging Sciences Centre, Brighton, East Sussex BN1 9RR, UK (4)Inst of Postgrad Med, Brighton and Sussex Medical School, Brighton, East Sussex BN1 9PH, UK

INTRODUCTION: There is evidence to suggest that the APOE e4 allele (which is associated with greater age-related cognitive decline, plus an increased risk of mild cognitive impairment and dementia) might paradoxically be associated with cognitive advantages earlier in life (Han and Bondi, 2008, Alzheimers Dement 4: 251-254). One explanation is that e4 carriers tend to overactivate certain brain regions, which drives cognitive advantages, but that the enhanced metabolic load has deleterious consequences over time. Further, our previous work suggests that nicotine might selectively benefi t e4 carriers, which raises the possibility of genotype-specifi c interventions to combat age-related declines in cognitive ability (Marchant, King, et al., 2010. Neuropsychopharmacology 35: 1090-1096). METHODS: We explored performance on a prospective memory (PM) task in young adults (age 18-24) with and without 1mg nicotine (nasal) using a within-subjects design. Both sessions were imaged using fMRI. Participants performed a routine ongoing task while remembering to make a specifi c response (the PM instruction) to particular stimuli embedded in the task. RESULTS: Nicotine effects varied according to APOE status. Reaction times to the PM cue were improved under nicotine in e4 carriers, but not in e3 carriers. Activations in medial BA10 (previously implicated in PM) differentiated e4 from e3 carriers on PM trials. In one BA10 subregion greater deactivations were observed in e4 carriers, which could refl ect a need for greater downregulation of resting state networks in this group. Activity in a neighbouring BA10 subregion showed nicotine effects specifi c to e4 carriers. Furthermore, activity in right hippocampal formation was only seen in e4 carriers receiving nicotine. CONCLUSIONS: These results point to genotype-specifi c differences in neural activity during PM. These differences might be due to a greater need to downregulate resting state networks in e4 carriers so as to engage with the task. Also, nicotine might enhance PM performance in e4 carriers through effects in BA10 and hippocampal regions. Exploring these mechanisms could prove benefi cial for remediating cognitive decline in e4 carriers. This work was funded by a BBSRC grant to Prof J. Rusted (BB/H000518/1). ABSTRACTS A29

MD01

A DIMERIC INHIBITOR OF THE NMDA-R/PSD-95/NNOS INTERACTION REDUCES INFLAMMATORY PAIN WITHOUT DISRUPTING MOTOR OR COGNITIVE PERFORMANCE: COMPARISON WITH THE NMDA RECEPTOR ANTAGONIST MK-801 Andreasen JT, Dept of Drug Design and Pharmacology, Faculty of Health and Medical Sci, Univ of Copenhagen, Universitetsparken 2 DK-2100 Copenhagen Denmark, DK-2100 [email protected] Bach A(1), Gynther M(1), Mogensen J(2), Strømgaard K(1), Pickering DS(1). (1) Dept. of Drug Design and Pharmacology, Univ of Copenhagen, Denmark. (2) Unit for Cognitive Neurosci, Dept. of Psychology, Univ of Copenhagen, Denmark.

Development and maintenance of chronic pain states involves excessive NMDA receptor (NMDA-R) activation. Accordingly, broad-spectrum NMDA-R antagonism displays anti-nociceptive action in humans and animal models of chronic pain. However, NMDA-R antagonism is associated with disturbances in cognitive and motor function. NMDA-R activation leads to activation of the enzyme neuronal nitric oxide synthase (nNOS) resulting in an increased nitric oxide (NO) production, and NMDA-R-mediated excessive NO production is known to be involved in the central sensitization that occurs in chronic pain states. NMDA-R-mediated activation of nNOS depends on a scaffolding protein, postsynaptic density protein-95 (PSD-95). PSD-95 binds to the NMDA-R as well as to nNOS, thereby mediating a specifi c association between NMDA-R activation and NO production. An alternative approach to modulate the NMDA-R-related activity is therefore to perturb the NMDA-R/ PSD-95/nNOS interaction, i.e. decreasing NMDA-R-mediated NO production without interfering with the NMDA-R ion channel function. We have developed a new series of compounds that perturb the NMDA-R/PSD-95 interaction. These compounds display unprecedented affi nities towards PSD-95. By dimerization of two pentapeptides and subsequent optimization we developed potent and highly selective PSD-95 inhibitors. Here, we compared the effects of one of our PSD-95 inhibitors, the O-dimer, and the selective NMDA-R antagonist MK-801 on mechanical hyperalgesia in the Complete Freund’s Adjuvant (CFA) model of chronic infl ammatory pain. To examine side-effect profi les we also compared the effects of MK-801 in the rotarod test of motor performance, as well as in the modifi ed Y-maze test of attention and the social transmission of food preference (STFP) test of long-term memory. When administered concurrently with CFA, both MK-801 (MED=0.1 mg/kg) and the O-dimer (MED=1.0 mg/kg) prevented the development of CFA-induced hyperalgesia as measured with the von Frey test of mechanical hyperalgesia 1 hour and 24 hours after treatment. Moreover, the O-dimer (MED=1.0 mg/kg) was found to reverse CFA-induced hyperalgesia when administered 24 hours after CFA treatment, an effect lasting for at least 3 days. At doses showing antinociceptive effects in the von Frey test, MK-801 induced motor defi cits in the rotarod test as well as cognitive defi cits in the modifi ed Y-maze and STFP tests. By contrast, at doses up to 60 mg/kg the O-dimer was devoid of side-effects in these tests. The data suggest that PSD-95 inhibition is a feasible strategy to prevent both development and maintenance of chronic infl ammatory pain, while avoiding NMDA-R antagonism-related side-effects. The study was supported by the Lundbeck Foundation.

MD02

MODIFICATIONS TO THE 5-CHOICE SERIAL REACTION TIME TASK REDUCES IMPAIRMENTS IN ATTENTION AND IMPULSE CONTROL ASSOCIATED WITH NMDA RECEPTOR ANTAGONISM Benn A, Physiology and Pharmacology, Univ of Bristol, University Walk, Bristol BS8 1TD [email protected] Robinson E, Dept Pharmacology and Physiology, Univ of Bristol, University Walk Bristol BS8 1TD

NMDA antagonism has been used in rodents to model the cognitive impairments seen in schizophrenia. Previous studies, using the 5-choice serial reaction time task (5-CSRTT) have reported defi cits in attention and impulse control following systemic administration of NMDA antagonists. The standard version of the 5-CSRTT uses a fi xed inter-trial interval (ITI), normally 5 seconds, which precedes the presentation of the light cue. In this task, acute treatment with NMDA antagonists typically induce a reduction in accuracy, increase in omission level, and an increase in premature responses (Smith et al 2011, Psychopharmacology, 217, pg 255-269). We and others have observed that animals performing the 5-CSRTT under a fi xed ITI exhibit stereotypic motor behaviour to control their response to the stimulus. We hypothesised that performance defi cits in the 5-CSRTT induced by NMDA antagonism, may be mediated by effects on this behaviour. In this study we have investigated the effects of four NMDA antagonists in a non-paced 5-CSRTT, where stimulus presentation occurs after a variable ITI (VITI) of 4, 5, or 6 seconds (presented randomly). This is designed to reduce the ability to use timing behaviour and to increase the attentional demand of the task. Lister-Hooded rats (n=12, 350-450g) were trained to a stable level (>80% accuracy, <20%omissions) in a non-paced VITI version of the 5-CSRTT, before acute treatment with each drug. Ketamine (0.1-1.0mg/kg), dizocilpine (MK801 0.01-0.1mg/kg), phencyclidine (PCP 0.3-3.0mg/kg), and memantine (0.1-3.0mg/kg), were administered systemically, with each animal receiving all doses in a randomized, latin-square design. Our results show that MK801 treatment induced a signifi cant effect on premature responses and omissions (F(1.5, 16.0)=5.02, P=0.029 and F(3.0, 33.0)=7.20, P=0.001), with increases at 0.03 mg/kg (P=0.034) and 0.1 mg/kg (P=0.021) for premature responses, and a reduction at 0.03 mg/kg for omissions (P=0.006), compared to vehicle treated controls. Memantine increased omissions (F(1.1, 12.3)=12.19, P=0.004), and premature responses (F(3.0, 33.0)=5.15, P=0.005) at the highest doses. Accuracy was not affected by either MK801 or memantine, and treatment with ketamine and PCP failed to induce any signifi cant impairment in task performance. Our results show that none of the NMDA antagonists affected attention, and only MK801 increased premature responses in animals performing a non-paced version of the 5-CSRTT. We have shown that using a VITI reduces defi cits in impulse control and attention, usually observed with NMDA-antagonism. This suggests that some of the performance defi cits observed in normal animals following NMDA antagonist treatment, occurs from effects on timing behaviours rather than specifi c cognitive impairment. A30 ABSTRACTS

MD03

PRECLINICAL MODELLING OF ATTENTIONAL DEFICITS AND IMPULSIVITY OF RELEVANCE TO ADHD: PHARMACOLOGICAL EVALUATION STUDIES USING THE 5-CSRTT AND IMPLICATIONS FOR THERAPY OF ADULT ADHD Tomlinson A, School of Pharmacy, Univ of Bradford, Richmond Rd, Bradford, West Yorkshire BD7 1DP [email protected] Marshall KM (1) Neill JC (1) (1) b-neuro at the Univ of Bradford, Bradford, BD7 1DP, UK

Cognitive defi cits remain an unmet clinical need and are indicative of outcome in many psychiatric disorders including ADHD (Millan et al., 2012 Nat Rev 11; 141-168). Various cognitive domains, including executive function, attention, information processing, and working memory, are impaired in ADHD. More females are affected by ADHD than males in adulthood, women show higher rates of comorbidities such as depression, anxiety, and cognitive impairment (Biederman et al., 1994, Psych Res 53; 13-29). The 5-choice serial reaction time task (5-CSRTT) is used in rodents to assess attentional function and impulsivity; performance may be modifi ed using pharmacological agents. The aim of the current study was to investigate the effects of psychostimulant and non-stimulant drugs on attention, impulsivity and performance by modifying 5-CSRTT task parameters in animals trained to a set criterion. The effects of acute methylphenidate (0.1, 0.5, 1.0 mg/kg i.p) and atomoxetine (0.1, 0.5, and 1.0 mg/kg i.p) were assessed in the 5-CSRTT in adult female Lister-hooded rats. Impulsivity measures included; premature responding, attentional measures included; % omissions and % accuracy, latency measures included; correct response and incorrect response latencies. Animals were challenged on test days by increasing the inter-trial interval (ITI) to 10s or 20s. Female adult rats challenged in the 5-CSRTT acutely treated with atomoxetine showed a dose-dependent reduction in impulsivity as measured by a signifi cant reduction in premature responding (0.5 mg/kg, p<0.001 and 1.0 mg/kg, p<0.001). Atomoxetine (0.5 mg/kg) produced a signifi cant reduction (p<0.05) in one of the attentional measures (% omissions), but no difference in % accuracy. Atomoxetine produced a signifi cant increase in correct latency (1.0 mg/kg, p<0.05) and no difference in incorrect latency compared with vehicle treated animals. Treatment with methylphenidate at the highest dose (1.0mg/kg) signifi cantly improved accuracy (p<0.01), reduced % omissions and signifi cantly increased premature responding (p<0.05). Methylphenidate signifi cantly decreased correct response latency at the highest dose (1.0 mg/kg p<0.01), and increased the incorrect response latency at 0.5 and 1.0 mg/kg (p<0.05, p<0.01 respectively). Atomoxetine decreased impulsivity in the 5-CSRTT (as measured by premature responses) and produced marginal increases in sustained attention (as measured by a reduction in % omissions). Methylphenidate enhanced sustained attention at higher doses measured by an increase in accuracy (correct responses), however at this dose, methylphenidate also increased impulsivity. Atomoxetine enhanced sustained attention and reduced impulsivity methylphenidate only enhanced sustained attention. This work provides evidence for the involvement of both noradrenaline and dopamine in the pathophysiology of ADHD.

MD04

THE EFFECTS OF THE L-TYPE CAV CHANNEL BLOCKER, NIFEDIPINE, ON BEHAVIOUR OF WILDTYPE AND NK1 RECEPTOR ‘KNOCKOUT’ MICE DIFFER IN THE 5-CHOICE SERIAL REACTION TIME TEST Stanford SC, Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT [email protected] Weir RK (1), Yan TC (2), Grabowska EM (1), Grimmé AJ (2), Amini S (2), Stephens DN (3), Hunt SP (1), Dudley JA (1) (1) Dept of Cell & Develop Biol, UCL, Gower St, London, WC1E 6BT (2) Dept Neurosci, Physiol & Pharmacol, UCL, Gower St. London WC1E 6BT (3) School of Psychology, Univ Sussex, Falmer, Brighton, BN1 9QG

Core diagnostic features of Attention Defi cit Hyperactivity Disorder (ADHD) are inattentiveness, impulsivity and hyperactivity, but perseveration is also common. When compared with wildtypes, all these behaviours are increased in mice with functional ablation of the substance P-preferring receptor gene (NK1R-/-) (Yan et al., 2011. PLoS One 6:e17586; PMID: 21408181). In vitro activation of NK1R modulates the opening of L-type (Cav) channels, which are prevalent in brain regions that govern cognitive performance and response control (the prefrontal cortex and striatum). Here, we compared the effects of the L-type channel blocker, nifedipine, in wildtype and NK1R-/- mice in vivo. Male mice of both gentoypes (129/Sv X C57BL/6 crossed with an outbred MF1 strain) were trained to baseline criterion in the 5-Choice Serial Reaction Time Task, which was used to score %omissions (an index of inattentiveness), %premature responses (a form of impulsivity) or perseveration. Untreated mice were then tested using a variable inter-trial interval (VITI) schedule (2s – 15s). Next, the mice experienced a series of once-weekly VITI tests. These were carried out with either no injection of vehicle or drug, or 30 min after an intraperitoneal injection of either vehicle (20% Tween 80 in 0.9% saline; 10 mL/kg) or nifedipine (3 or 10 mg/kg). The sequence of these test conditions was counterbalanced across all animals. %Premature responses and perseveration were reduced, but the %omissions was increased, by nifedipine in both genotypes. However, it is striking that wildtypes were more sensitive to the effects of nifedipine than NK1R-/- mice, especially in respect of their %premature responses (F(1,18)=5.29; P<0.05) and %omissions (F(3,56)=3.19; P=0.03). We propose that activation of NK1R can modify the infl uence of L-type Cav channels on cognitive performance and response control. Disruption of this functional interaction could contribute to performance defi cits in some ADHD patients, especially those with polymorphism of the tacr1 (NK1R) gene. This work was funded by the Medical Research Council (UK)

MD05

A PROOF-OF-CONCEPT INVESTIGATION OF GENOTYPE-DEPENDENT NORADRENERGIC EFFECTS ON ATTENTION Chan KFD, Clinical Medicine, Brighton and Sussex Med Sch, Univ of Sussex ,Brighton, East Sussex BN1 9PX [email protected] Gibbs AA(1), Somal SK(2) (1) Clinical Imaging Sciences Centre, Brighton and Sussex Med Sch, Univ of Sussex, Falmer, Brighton BN1 9RR; (2) Clinical Medicine, Brighton and Sussex Med Sch, Univ of Sussex, Brighton, East Sussex, BN1 9PX

Introduction: Several genes have been identifi ed to be associated with human cognition, hence they may have a role in contributing to individual vulnerability to psychiatric disorders. We are particularly focusing on two genetic polymorphisms involved in catecholamine neurotransmission likely to be related to cognitive function - A2B adrenergic autoreceptor (ADRA2B) insertion/deletion and val158met COMT gene polymorphisms. It has been shown that in the presence of the ADRA2B deletion, the relative memory impairment is abolished in COMT val/val individuals (Gibbs AA et al , 2010, the Journal of the European College of Neuropsychopharmacology 2010;20(4):272-275). Therefore, we administered Reboxetine to explore whether genetic variation would contribute to the effects of noradrenergic drugs on cognition. We hypothesized that Reboxetine would enhance cognitive performance in COMT val/val individuals. Methods: 48 healthy white British men between the age of 18 and 30 took part in the experiment. Buccal swabs were obtained for DNA analysis in relation to COMT and ADRA2B polymorphisms. They have been allocated into two groups in which half of them took 1 dose of 4mg Reboxetine while the other half had a placebo in a double blind procedure. An attentional blink task was carried out 2 hours later: participants were asked to identify two green target words (T1 and T2) from other distracter words. We also explored the contribution of emotional salience to attentional processes by varying the emotional valence of the T2 words. All T1 words were neutral words while T2 could be neutral, positive or aversive. The primary outcome measures were the percentage of correct T1 and T2 detection. Results: T2 detection accuracy was better for negative [T(39)=9.691,P<0.001] and positive words [T(39)=7.165,P<0.001] than natural words. T2 detection also improved when the time lag between 2 targets words increased. [F(2,76)=229.6,p<0.001]. However, there was no main effect of group (reboxetine, placebo) on T2 detection. The detection of positive (t(38)=1.125,P=0.268, negative (t(38)= 0.581,P=0.565) and neutral words (t(38)=0.159,p=0.875) was not affected by Reboxetine. Genetic analysis is pending but it is predicted that Reboxetine will improve attention in COMT val/val carriers without ADRA2B deletion. Conclusions: We found that T2 detection was enhanced for positive and negative words, compared to neutral, in line with previous studies investigating affective modulation of the attentional blink. Conclusions regarding the impact of genetic variation on these processes are deferred pending analysis of these data. Sources of fi nancial sponsorship: Brighton and Sussex Medical School ABSTRACTS A31

MD06

A PROOF-OF-CONCEPT INVESTIGATION OF GENOTYPE-DEPENDENT NORADRENERGIC EFFECTS ON MEMORY Somal SK, Clinical Medicine, Brighton and Sussex Med Sch, The Audrey Emerton Bldg, Eastern Rd, Brighton, East Sussex BN2 5BE [email protected] Gibbs AA (1), Chan KFD (2) (1) Brighton and Sussex Med Sch, Clinical Imaging Sciences Centre, Univ of Sussex, Falmer, Brighton BN1 9RR (2) Brighton and Sussex Med Sch, The Audrey Emerton Bldg, Eastern Rd, Brighton, East Sussex BN2 5BE

Background: The impact of genetic variation on cognition in healthy humans is increasingly recognised. A COMT gene polymorphism that encodes the enzyme responsible for degradation of PFC catecholamines is associated with an inverted-U-shaped relationship between dopamine levels and cognitive function, with better performance seen in low COMT activity (Met/Met) individuals than high COMT activity (Val/Val). An association between the ADRA2B gene deletion polymorphism and enhancement of emotional memory compared to neutral has also been observed. The interaction between these polymorphisms may be more signifi cant in mediating individual differences, as impaired memory performance in COMT val/val individuals was improved if they possessed the ADRA2B deletion variant but had no effect in COMT val/met or met/met. This suggests drugs that boost noradrenergic transmission may enhance cognition, but that this may be dependent on both COMT and ADRA2B genes. This investigation is to collect proof of concept data to explore whether the effects of noradrenergic drugs are mediated by epistatic effects between COMT and ADRA2B polymorphisms. Methods: A double-blind, randomised, placebo-controlled, between-group intervention was carried out in 49 healthy white male volunteers using a 4mg dose of Reboxetine, a selective noradrenaline reuptake inhibitor. All participants carried out a buccal swab to enable genotyping for the polymorphisms. Two hours after intervention, all participants were administered a memory task involving viewing pictures that varied in valence and arousal. This incorporated an incidental encoding, free recall and recognition test. Results: Results showed enhanced recall of emotional stimuli compared to neutral, particularly negative stimuli for both Reboxetine and placebo groups. For recognition, a drug x valance interaction was observed whereby Reboxetine impaired memory for negative stimuli relative to positive, in comparison to placebo, based on the discrimination index (p). Although there was no main effect on discrimination, Reboxetine was found to have a signifi cant effect on recognition memory via the response bias (B) for neutral, positive and negative stimuli. Specifi cally, participants in the Reboxetine group demonstrated a signifi cantly more conservative response bias, irrespective of valence [F(1, 28)=5.6, p=0.02]. Genetic analysis is ongoing and these data will be presented on the poster. Conclusions: Previous research evaluating the effect of Reboxetine on cognition in healthy individuals and in disorders such as Schizophrenia, have predominantly investigated recall, rather than recognition memory. These studies found no effect, however our data thus far suggest that Reboxetine may impact on memory performance but this may operate via recognition memory processes rather than recall.

MD07

A PHARMACOLOGICAL EVALUATION OF EFFICACY TO REVERSE DELAY DEPENDENT EPISODIC MEMORY DEFICITS IN THE OBJECT PLACE CONTEXT TASK IN FEMALE RATS Fawcett H, B-Neuro, Univ of Bradford, Richmond Rd, West Yorkshire BD7 1DP [email protected] Grayson B(1) Neill JC(1) (1)Univ of Bradford, Richmond Road, BD7 1DP

Introduction: Episodic memory is the ability to recollect an event in terms of time and location (What? Where? When?) (Tulving. E. 2002 Annual Review Psychology. 53:1-25).Impaired episodic memory is a debilitating cognitive defi cit in Alzheimer’s disease, schizophrenia and other psychiatric and neurological disorders (Romain et al, 2010. Int J Neuropsych. 13:1011-1020; Backman et al, 2001 Brain. 124:96-102). Most animal tests for investigation of cognitive function of relevance to psychiatric disorders do not test the what? Where? and when? elements that symbolise episodic memory in human tests (Romain et al, 2010. Int J Neuropsych. 13:1011-1020). One task that does represent these components is the object place context task (OPC) as this requires consecutive incorporation of memory for object, place and context (i.e. What? Where? When?) Aim: To investigate the effect of a range of pharmacological agents on cognitive performance in the OPC task. Method: Female hooded-Lister rats were treated with saline (i.p.), the atypical antipsychotic risperidone (0.1mg/kg i.p.), psychostimulant nicotine (0.1 and 0.2mg/kg s.c.), AChEI donepezil (0.1 and 1mg/ kg i.p.), or the irreversible MAOI selegiline (1 and 2.5mg/kg i.p.), 30 min prior to testing. Testing consisted of sample phase 1 whereby rats explore two novel objects in a novel context followed by an inter-trial-interval (ITI) of 1 min; followed by sample phase 2, whereby rats encounter a novel context with familiar objects in opposite locations to sample phase 1; followed by a time delay of 1h. In the test phase, rats encounter a familiar context with 2 identical familiar objects; however one object has not been seen in a specifi c location in the test phase context. All 3 phases consist of a 3 min exploration time. Data are expressed as the mean ± S.E.M. (n=8-10) and analysed by paired Student’s t-test. Results: There were no differences in exploration time(s) of the two objects in either sample phase following any treatment. In the test phase there were no differences in the exploration time(s) of the two identical objects following treatment with vehicle, risperidone or nicotine. However, following treatment with donepezil (0.1 mg/kg) and selegiline (2.5 mg/kg), rats spent signifi cantly (P<0.05) more time(s) exploring the object in the new compared with the familiar location. Conclusion: Donepezil (0.1mg/kg) and selegiline (2.5mg/kg) but not risperidone and nicotine improved episodic memory in the OPC test. This test may have considerable value in the assessment of episodic memory defi cits disrupted in several neurological and psychiatric disorders. Financial Sponsorship; b-neuro, University of Bradford A32 ABSTRACTS

MD08

THE INFLUENCE OF ANXIETY AND DEPRESSIVE SYMPTOMS ON THE ACCESS OF EMOTIONAL STIMULI TO AWARENESS – A STUDY USING CONTINUOUS FLASH SUPPRESSION (CFS) Capitão LP, Dept of Psychiatry, Univ of Oxford, Neurosciences Bldg, Warneford Hospital Headington OX3 7JX [email protected] Underdown S(1), Vile S(1), Yang E(2), Harmer CJ(3) & Murphy SE(3) (1) Dept of Experimental Psychology, Univ of Oxford, South Parks Road, OX1 3UD (2) Dept of Psychology, Vanderbilt Univ, 111 21st. Avenue South, Nashville, USA (3) Dept of Psychiatry, Warneford Hospital, Headington OX3 7JX

Prioritising the processing of potentially threatening stimuli has clear evolutionary value. There is some evidence that, in both healthy and clinical populations, there is an attentional bias towards threat, even under conditions of restricted awareness. However, existing paradigms are limited since it is not always possible to confi rm that the stimuli have been presented subliminally or preconsciously. Continuous Flash Suppression (CFS) is a recently developed variant of binocular rivalry, which is aimed at ensuring complete visual suppression of target stimuli. In CFS, a low contrast target is presented to one eye, whereas high-contrast fl ashing patterns are presented to the other eye, resulting in initial suppression of the target image. The time that a target takes to be identifi ed can be used to determine its potency to compete for awareness. Previous studies employing CFS show that fearful faces are faster to reach consciousness (Yang et al. 2007, Emotion 7: 882-886). The aims of this study are two-fold: (1) replicate the preferential access of negative information to awareness using CFS and (2) investigate whether endogenous factors such as subclinical mood and anxiety infl uence the access of emotional information to consciousness. Forty-eight healthy volunteers completed a CFS task, in which fl ashing patterns of Mondrians were presented to one eye, and a neutral, fearful or happy face was presented to the other eye. The faces were presented in one of the four quadrants of a square and subjects were asked to identify its location as quickly as possible. Results showed a main emotion effect [F(2,94) = 6.487, p=0.002], with fearful faces being signifi cantly faster than happy faces to reach awareness (p=0.002). There was also a positive correlation between trait anxiety and depressive symptoms and reaction times to fearful faces (compared with happy) [rs =0.399, p=0.005 and rs=0.305, p=0.035, respectively], indicating that higher anxiety traits and depressive symptoms were associated with an increased relative speed to detect fear in comparison to happiness. These results provide additional evidence that negative faces gain preferential access to awareness under strong suppression. Additional studies are needed in order to clarify the infl uence of low-level features vs. emotional salience on this ‘fear advantage effect’. Nevertheless, these fi ndings suggest that endogenous factors such as predisposition to anxiety and low mood can infl uence the selection of facial expressions for conscious perception. This paradigm has therefore potential to test the effect of serotonergic manipulations such as SSRI administration, shown previously to infl uence early emotion processing stages. The student in charge of this study is funded by the Portuguese Foundation for Science and Technology (FCT) and the research costs were covered by the Departments of Psychiatry and Experimental Psychology, University of Oxford, England.

MD09

OPIOID INDUCED CHANGES IN MEMORY FUNCTIONING: A RANDOMISED, CONTROLLED, CROSS-OVER STUDY IN PALLIATIVE CARE PATIENTS Kamboj SK, Psychology, UCL, Gower St London WC1E 6BT [email protected] Conroy L (1) ,Carrol E (1), Tookman A (2), Jones L (2), Curran HV (1) UCL (2) Marie Curie Palliative Care Research Unit, Hampstead, London, UK

Opioid are potent analgesia but have a variety of other (side-) effects on psychomotor functioning. Given the use of opioids for acute and chronic pain in an increased variety of settings, clinicians have become more attentive to possible deleterious effects of opioids on cognitive functioning. Existing studies examining the effects of opioids on memory have produced inconsistent results (see references in Kamboj et al, 2005 Pain, 117, 388-395). Previously we found that patients receiving long- acting opioid therapy showed anterograde and retrograde memory impairments following immediate release morphine treatment (Kamboj et al, 2005). Here, we aimed to replicate and extend our fi ndings by investigating potential mechanisms of memory dysfunction following immediate release opioid treatment in patients receiving long-acting opioids. In a randomised, placebo controlled cross-over design, performance on word pair and prose memory tasks was measured before and after a dose of the patient’s usual immediate-release opioid medication (morphine or oxycodone) or placebo in patients receiving long-acting opioid (n=20). Performance on a fi nal ‘interference’ word list, which was designed to produce memory errors (intrusions from a previously learned word pair) was also measured. Data was analysed using a repeated measures ANOVA using within subject factors of treatment (placebo, opioid), time (pre-, post-) and word pair relatedness (related, unrelated) or paired sample t-test (interference list after placebo or opioid). While we did not observe anterograde or retrograde amnesia for prose memory, performance on unrelated words pairs was signifi cantly impaired after immediate-release opioid treatment (p=0.023). Alternatively, performance on the fi nal ‘interference’ word list was better following immediate release opioid (p=0.026), although this was not accompanied by a greater number of errors. These fi ndings suggest that when immediate-release opioid medication is used to supplement long acting opioids, discrete areas of memory impairment and enhancement can be found. Impairment may be especially likely on demanding cognitive tasks. Alternatively, improved cognitive performance on certain memory tasks may be secondary to pain relief. The results of this study may help patients and clinicians make more informed decisions about the use of ‘break-through’ opioid medication. Financial support: This project was supported by funding from the University College London Graduate School ABSTRACTS A33

ME01

QUALITY OF CASE REPORTS OF ADVERSE DRUG REACTIONS WITH PSYCHOTROPIC DRUGS Talat B, Dept of Psychological Services, Somerset Partnership NHS Foundation Trust, UK, Academic Centre, College Keep, 4-12 Terminus Terrace, SO14 3DT bilal. [email protected] Mayers A(1), Baldwin DS (2). (1) Psychology Group, School of Design, Engineering and Computing, Bournemouth Univ, UK. (2) Faculty of Medicine, Univ of Southampton, UK

Introduction: Case reports of adverse reactions with psychotropic drugs can be useful in raising hypotheses about pharmacological effects, to be tested with more rigorous study designs. However such reports have signifi cant methodological drawbacks, making it hard to determine causality, and leading many authorities to question their value. Method: We undertook a systematic assessment of the quality of all case reports and small case series published within the journal Human Psychopharmacology over a period of 25 years. For reports of adverse drug reactions, modifi ed Bradford-Hill criteria for causality (for consistency, strength, specifi city, temporal relationship, and plausibility) were used to ascertain the quality of the account. Reports which had been cited 10 times or more (according to ISI Web of Knowledge) by December 2010 were examined in more detail, to assess their overall contribution in extending understanding and infl uencing clinical practice. Results: Forty reports of adverse drug reactions were published over 25 years. Subsequent re-challenge after withdrawal of the implicated drug was uncommon (7 reports). Dose-response relationships were explored in 10 reports. A report of two cases of inhibition of trimipramine metabolism by paroxetine, a single case report of hypertension with sulpiride, a case series (n=6) of bruxism with SSRIs, a case series (n=2) of restless legs syndrome with mirtazapine, and a case series (n=3) of discontinuation symptoms after paroxetine were suffi ciently robust for confi dence in probable causality; but other reports provided insuffi cient evidence to determine likely causality. Eleven reports had been cited more than 10 times. The fi ve most frequently cited reports of adverse drug reactions described movement disorders, suicidal thoughts and discontinuation symptoms with SSRIs; neuroleptic malignant syndrome with risperidone; and abuse of zopiclone: the clinical relevance was high, but their quality was not consistently greater than other less frequently cited reports. Conclusion: Nearly all reports of adverse drug reactions, published in a single journal over 25 years, were insuffi ciently robust to demonstrate probable causality. Reports which have been cited frequently become infl uential because of their potential clinical relevance, rather than due to their methodological quality. Funding No funding was sought or provided for this study.

ME02

‘AS REQUIRED’ DRUG PRESCRIBING IN ACUTE INPATIENT PSYCHIATRY: A RETROSPECTIVE STUDY – PRELIMINARY FINDINGS Preeti G, Old Age Psychiatry, Oxleas NHS Foundation Trust, The Upton Centre, 14 Upton Road, Bexleyheath DA68LQ [email protected] Rasquinha N(1), Dratcu L(1) (1)Maudsley Hospital, South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AZ

Introduction: Polypharmacy is invariably present in the acute setting, where PRN (pro re nata) or ‘as required’ medication is frequently used for managing acutely disturbed behaviour. Benzodiazepines or antipsychotics are often the drugs of choice. However, PRN medication increases the risk of adverse reactions, drug interactions and other complications. This audit was designed to assess PRN prescribing in an acute unit with a view to establishing parameters that could promote safer and more effective drug prescribing. Methods: We reviewed prescription charts and clinical records of 50 patients consecutively discharged from an acute adult male-only unit at Maudsley Hospital. We designed and piloted an audit tool to collect data on demographics, diagnosis, co-morbidity, and both regular and PRN medication during the two fi rst weeks of their admission. Descriptive analysis was used to examine results of this ongoing study. Results: Preliminary results [n=38; age 37.6 ± 9.8, 22- 63 (mean ± SD, range)] have shown that 37% of patients had relevant medical co-morbidity. 100% of patients were prescribed PRN drugs, the number of PRN drugs prescribed being 3.6 ± 1.1, 1-6 per patient. Most PRN prescriptions (77%) were psychotropics, of which 47% were benzodiazepines, 34% antihistaminic hypnotics, 17% non-benzodiazepine hypnotics (Z-drugs) and 3% antipsychotics. Benzodiazepines were used intermittently on 42.5% of patients but no patient received the full prescribed dosage on a daily basis. Antihistaminics were used intermittently in 67% of the patients and everyday only in 3% of the group. Hypnotic (Z-drugs) were used intermittently in 45% of patients and at the full prescribed dose in only 6%. PRN antipsychotics were used intermittently in 67% of patients to whom they were prescribed. There were no incidents or complications involving drug prescribing for the duration of the period studied. Conclusion: The study revealed moderate use of PRN benzodiazepines, hypnotics and antipsychotics, prescribed alone or in combination. Very few of these drugs were used continually at the full prescribed dose for the duration of the study, suggesting that psychotropic PRN prescribing in the acute setting can be limited to fewer drugs prescribed for shorter periods, and also that prudent psychotropic PRN prescribing is likely to reduce risk of complications associated with polypharmacy. Further analysis will examine the infl uence of co-morbidity on psychotropic and non-psychotropic co-prescribing in the acute setting.

ME03

A RETROSPECTIVE STUDY OF CLOZAPINE IN EMOTIONALLY UNSTABLE PERSONALITY DISORDER Picchioni M, St Andrew’s Academic Centre, Kings College London, Inst of Psychiatry, The Braye Centre, Cliftonville Rd, Northampton NN1 5BW catherine.frogley@ kcl.ac.uk Frogley C(1) Anagnostakis K (2) Mitchell S(2) Mason F(1) Dickens G(1) Picchioni M(1) St Andrew’s Academic Centre, The Braye Centre, Cliftonville Road, Northampton, NN1 5BW (2) St Andrew’s Healthcare, Billing Road, Northampton, NN1 5BW

Introduction: Emotionally unstable (borderline) personality disorder is a common debilitating disorder for which there are limited effective treatments. Emerging evidence suggests that the second-generation antipsychotic, clozapine, may be effective in the treatment of this disorder. This retrospective study aimed to identify evidence that clozapine produced a signifi cant reduction in symptoms and clinical gains in patients with severe emotionally unstable personality disorder, and to explore evidence for possible mechanisms of action and safety. Methods: We retrospectively examined the case notes of all female patients with a primary diagnosis of emotionally unstable personality disorder who had started treatment with clozapine between January 2002 and July 2010. All patients were past or current in-patients of St Andrew’s Healthcare. They did not need to be still taking clozapine and the cohort included patients who had since been discharged. Baseline routine clinical data was collected from the medical records and at six monthly intervals thereafter, up to a maximum of 18 months after starting clozapine. Patients were also interviewed to assess their experience of clozapine. Results: Twenty-two women agreed to participate. We found a signifi cant effect of clozapine across several domains. Symptom severity (BPRS), risk (START), number of days on enhanced observations, the use of additional anti-psychotic and anxiolytic medication and the number of aggressive incidents all signifi cantly improved following clozapine initiation. The greatest improvements appeared within the fi rst six months of clozapine treatment. There was however also a signifi cant increase in weight over the fi rst eighteen months. Thematic analysis of the womens’ views suggested two evaluative steps in clozapine therapy. Firstly many women perceived the effects of clozapine to be clearly benefi cial with a small number perceiving either a neutral or actively unhelpful effect. Secondly while side effects and inconvenience were common, they were often viewed as tolerable. Some women appeared to experience clozapine treatment as more facilitative then restrictive. Conclusion: The study represents, the largest single cohort of women treated with clozapine for emotionally unstable personality disorder and the longest follow-up time to date. The results suggest that clozapine is benefi cial for this group of patients. However, larger, randomised, blinded and controlled prospective studies are needed to confi rm these fi ndings. Funding: St Andrew’s Healthcare A34 ABSTRACTS

ME04

ATTITUDES OF UNDERGRADUATE STUDENTS TOWARDS RECREATIONAL DRUG USE AND MENTAL ILLNESS Loxton K, Welsh School of Pharmacy, Cardiff Univ, Redwood Bldg, Cardiff CF10 3NB [email protected] Deslandes RE (1), Deslandes PN (2) (1) Welsh School of Pharmacy (2) Pharmacy Dept, Whitchurch Hospital, Cardiff CF14 7XB

Introduction: The Royal College of Psychiatrists’ “Changing minds” campaign was established to address the stigma associated with mental illness. The aim of this investigation was to assess attitudes of undergraduate students towards mental illness, and to determine whether students believed that use of alcohol or recreational drugs impacted on mental health. Methods: The study used a self-completed questionnaire which surveyed attitudes towards mental illness and then asked whether the use of alcohol, cannabis, cocaine, heroin, ketamine, crystal meth, LSD or ecstasy could cause long-term mental illness. Responses were measured using a fi ve-point Likert scale consisting of “strongly agree”, “agree”, “don’t know”, “disagree”, and “strongly disagree”. Responses of strongly agree and agree were combined and reported together as “Agreed”. Convenience sampling was employed and questionnaires distributed to undergraduate students from Optometry, Physiotherapy and Humanities departments during lectures. The study was approved by a Cardiff University ethics committee. Results: A total of 438 questionnaires were distributed and 230 completed, a response rate of 53%. The response in optometry (76%) was signifi cantly greater than physiotherapy (51%) and humanities (41%) (p<0.01, Fisher’s Exact test). A larger proportion of respondents were female (77%, n=177) than male (23%, n=53). In response to attitude statements, 85% of students agreed that “Anyone can develop a mental illness” and 73% agreed that “Almost everybody will be affected either directly or indirectly by mental illness at some point”. When asked whether each recreational drug was associated with mental illness the percentage of respondents who agreed and the percentage that answered “Don’t know” respectively was alcohol 85% (9%), cannabis 80% (16%), cocaine 72% (27%), heroin 77% (23%), ketamine 60% (38%), crystal meth 65% (34%), LSD 62% (35%) and ecstasy 60% (34%). The percentage of females believing that ecstacy was associated with mental illness was signifi cantly greater than males (62% vs 53% p<0.01 Fisher’s Exact Test) other responses did not differ signifi cantly between degree subjects or gender. Conclusion: The students appeared to have an awareness of the prevalence of mental illness. A limitation is the inclusion of only two health science and one non-health science groups. As might be predicted, students appeared most confi dent in the effects of alcohol and cannabis (Cahill and Byrne, Ir Med J 2010:103;230-3), whilst the greatest number of “Don’t know” responses was to ketamine. Interestingly, despite the widespread culture of binge drinking in the UK, 85% of students agreed that alcohol use was associated with mental illness. Sources of funding: None

ME05

HOW MUCH DO DOCTORS KNOW ABOUT ALCOHOL CONSUMPTION AND ALCOHOL USE DISORDERS? Brandish EK, Clinical and Experimental Sciences (CNS and Psychiatry), Univ of Southampton Faculty of Medicine, Univ Dept of Psychiatry, Academic Centre, College Keep, 4-12 Terminus Terrace, Southampton SO14 3DT [email protected] Sheron N (1), Baldwin DS (2), Sinclair JMA (2) (1) Univ of Southampton Fac of Medicine, Southampton General Hospital, Tremona Road, Southampton SO16 6YD (2) Univ of Southampton Fac of Medicine, College Keep, 4-12 Terminus Terrace, Southampton SO14 3DT

Background: Alcohol use disorders make signifi cant economic and resource demands on health services. NICE guidance regarding management of alcohol related problems has been widely adapted by NHS Trusts, to produce local guidelines for the management of acute alcohol withdrawal and the continuing care of patients with alcohol use disorders. A working group of the Royal Academy of Medical Colleges is developing a consensus statement “Alcohol and Other Drugs: Core Medical Competencies”, with recommendations for competences to be incorporated into all postgraduate medical curricula. Methods: A 17-item questionnaire survey was developed to assess knowledge about national and local recommendations. A convenience sample of doctors across the spectrum of grades was sought, questionnaires being completed by both physicians and surgeons involved in the admission of patients to hospital. Results: 94 doctors completed the questionnaire: 9 consultants, 11 specialty registrars, 17 senior house offi cers and 57 Foundation doctors: 78 were working in medical roles and 16 in surgical roles. 9 questionnaires were incomplete (2 or more items missing) and therefore excluded. There was widespread lack of knowledge about the alcohol content of commonly consumed drinks (only 4.7% answered all 5 items correctly); and most (88.2%) misunderstood current recommendations regarding daily consumption. Most (80%) felt able to offer simple brief advice to patients. However performance on a test linking commonly encountered clinical vignettes to the most likely alcohol-related problems was poor (incorrect responses by 65%). Use of standardised alcohol assessment measures was sub-optimal (52.9%); confi dence in assessing the need for specialist input was low (52.9%); and less than half (48.2%) had recommended the involvement of specialist alcohol services in the management of their patients. Conclusions: A substantial proportion of surveyed doctors lacked confi dence in assessing and managing patients with alcohol use disorders. Widespread lack of knowledge about the alcohol content of alcoholic beverages, about current recommendations for ‘safe drinking’, and about the identifi cation of common alcohol-related problems emphasises the pressing need for targeted educational interventions. Funding: No funding was sought or granted for this survey. Dr Emma Brandish is supported by the University of Southampton National Institute of Health Research Academic Foundation Programme. ABSTRACTS A35

MF01

GLUTAMATE MICROSENSORS REVEAL ALTERED GLUTAMATE SIGNALLING IN HIPPOCAMPAL SLICES FROM A RAT NEURODEVELOPMENTAL MODEL OF SCHIZOPHRENIA King MV, School of Biomedical Sciences, Univ of Nottingham, Medical School, QMC, Nottingham NG7 2UH [email protected] Fone KCF – address as presenter

Post-weaning social isolation in the rat induces a range of behavioural and neurochemical alterations similar to those in schizophrenia (Jones et al. 2011 Br J Pharmacol 164 1162). Combined neonatal PCP administration may cause additional cognitive and PPI defi cits, thereby producing a more robust model of this disorder (Gaskin et al. 2011 J Psychopharmacol 25S A70). The current study utilised microsensors to investigate glutamate signalling in hippocampal slices from isolation reared and/or neonatal PCP-treated rats, since alterations in hippocampal glutamatergic neurotransmission are implicated in schizophrenia (Tamminga et al. 2010 Am J Psychiatry 167 1178). Male Lister hooded rats (CRUK) received saline vehicle (1ml/kg) or PCP HCl (10mg/kg) s.c. on PND7, 9 and 11, then from weaning (PND21) were housed in groups (4/cage) or individually. Vehicle-treated grouped (Veh-Gr), PCP-treated grouped (PCP-Gr), vehicle-treated isolate (Veh-Iso) and PCP-treated isolate (PCP-Iso) animals (n=7/group) underwent locomotor activity (LMA; PND57), novel object discrimination (NOD; PND58) and pre-pulse inhibition of the acoustic startle response (PPI; PND63) testing. Rats were killed by cervical dislocation (PND64-98) and individual 400μm hippocampal slices (Olzenziel et al. 2007 J Neurosci Meth 160 37) transferred to an interface chamber (Harvard Apparatus). Glutamate and null sensors (Sarissa Biomedical) were inserted into the CA1 region of the hippocampus to monitor basal extracellular glutamate, and responses to KCl (30, 60 and 120mM) and the glutamate reuptake inhibitor DL-threo-β-benzyloxyaspartic acid (TBOA, 200μM). Isolation rearing impaired NOD (n=7/group) and initial fi ndings (n=3/group) suggest PCP impaired PPI (P=0.0239 at 80dB pre-pulse, 2-way ANOVA), such that only PCP-Iso exhibited both NOD and PPI defi cits. Basal extracellular glutamate concentrations (n=3/group) were infl uenced by housing (P=0.0378, 2-way ANOVA) but not PCP treatment, being signifi cantly lower in Veh-Iso (1.411±0.281μM) than Veh-Gr (2.984±0.422μM; P<0.05 Bonferroni post-hoc). The response to TBOA also tended to be greater in Veh-Iso (215±37% of basal) than Veh-Gr (142±7%). Combined neonatal PCP administration and isolation rearing appears to produce more robust behavioural defi cits than either manipulation alone. Initial microsensor fi ndings advocate the use of this technique to compare ex vivo glutamate release in slices from different experimental conditions, and suggest isolation rearing may decrease extracellular glutamate concentrations within the rat hippocampus. Ongoing studies will confi rm the combined impact of neonatal PCP administration, but at present it appears that alterations in hippocampal glutamate may contribute to some of the observed cognitive defi cits. This research was funded by a University of Nottingham Early Career Research and Knowledge Transfer Award to M.V.K.

MF02

SUB-CHRONIC PCP ALTERS GABAA TRANSPORTER AND VESICULAR GLUTAMATE TRANSPORTER GENE TRANSCRIPTION IN THE FRONTAL CORTEX OF FEMALE LISTER-HOODED RATS Glasper JE, School of Pharmacy, Univ of Bradford, Richmond Rd, Bradford, West Yorkshire BD7 1DP [email protected] Harte MK(1), Atack J(2), Neill JC(1). (1) School of Pharmacy, Univ of Bradford, Richmond Road, Bradford BD7 1DP UK (2) Johnson and Johnson, Dept of Neuroscience, PRD, 2340 Beerse, Belgium

Introduction: Evidence for abnormalities of the GABAergic system in schizophrenia is accumulating with post-mortem human studies consistently reporting defi cits in neuronal GABA transport in GABAergic neurons of schizophrenia patients (Gonzalez-Burgos and Lewis, 2008, Schiz Bull, 34(5):944-61). GABAergic signalling plays a key role in cognition by controlling the frequency of neuronal fi ring. Dysfunction of this system is thought to partially explain the cognitive defi cits shown in schizophrenia (Gonzalez-Burgos et al, 2011, Neural Plast, 723184). We have consistently shown that a sub-chronic PCP treatment regime in rats induces long lasting cognitive defi cits accompanied by alterations in GABAergic markers in the prefrontal cortex and hippocampus (Neill et al, 2010, Pharmacol Ther 128: 419-432, Glasper et al, 2011, Supp J Psych 8:25 TD21). The aim of the current study was to investigate the effect of sub-chronic PCP on gene transcription, with a focus on GABAergic and glutamatergic transport mechanisms. Methods: Adult female hooded-Lister rats received bi-daily injections of PCP (2mg/kg i.p.) or vehicle (0.9% saline i.p.) for 7 days, followed by 7 days washout (N=5 per group). Following sacrifi ce, brains were removed on ice, the frontal cortex dissected out and placed into RNAlater solution, in preparation for RNA extraction and analysis. Briefl y, tissue was homogenised in 1ml Trizol reagent and RNA extracted using Invitrogen mini columns. After conversion to cDNA using a Qiagen reverse transcription kit, gene expression was quantifi ed using SYBr Green qRT-PCR using a GAPDH normalising gene. REST software was used to analyse the data. Results: Sub-chronic PCP produced signifi cant reductions in all GABA transporters (GAT-1, GAT-3 and Viaat) in the frontal cortex (p<0.05). Of the glutamate transporters studied, only vGLUT2 showed altered expression (p<0.05) with no signifi cant change in transcription of any other cell surface/vesicular glutamatergic transporters. Conclusions: Sub-chronic PCP reduced levels of vesicular and non-vesicular GABA transporter gene transcription in the frontal cortex. In contrast only cortical VGLUT2 transcription levels were signifi cantly reduced. Down-regulation of VGLUT2 has been shown to occur under conditions of prolonged decreased neuronal excitation (De Gois et al 2005, J Neurosci, 25: 7121–7133). These preliminary fi ndings suggest that prolonged neuronal inhibition through impaired GABAergic transport, combined with a lack of compensatory glutamatergic transcriptional upregulation in the frontal cortex may play a role in the cognitive defi cits found in the sub-chronic PCP model. Defi cits in GAT-1 in the sub-chronic PCP rat cortex are consistent with those shown in post-mortem DLPFC of patients with schizophrenia. Acknowledgement: James Glasper is in receipt of a postgraduate studentship part-funded by Johnson and Johnson (Janssen) and part-funded by b-neuro at the University of Bradford. A36 ABSTRACTS

MF03

DEFICITS OF THE NEURONAL MARKER N-ACETYLASPARTATE IN THE FRONTAL CORTEX AND VENTRAL HIPPOCAMPUS FOLLOWING SUB-CHRONIC PHENCYCLIDINE TREATMENT IN THE FEMALE RAT Marsh S, School of Pharmacy, Univ of Bradford, Bradford, West Yorkshire, BD7 1DP, [email protected] Cunningham A, Keizel A, Keizel M, Salim A, Neill JC, Harte MK – addresses as presenter

Introduction: Schizophrenia is a chronic psychiatric disorder characterised by positive, negative and cognitive symptoms. Although the exact cause remains elusive there is substantial evidence for neuronal dysfunction in the brains in patients with the disorder. N-acetylaspartate (NAA) is present in high concentrations in the CNS and is considered to be a general marker of neuronal loss and/or cellular dysfunction. Numerous magnetic resonance studies have shown reductions in levels of NAA in schizophrenia, with defi cits correlated to disease severity. Studies have also demonstrated recovery of NAA levels following acute brain injury. Further studies have also reported increases in NAA following pharmacological therapy. Taken together these studies demonstrate its potential use as a biomarker for assessing restoration of neuronal function following successful treatments (Demougeot et al., 2001, J. Neurochem. 77, 408– 415). We have consistently demonstrated that sub-chronic phencyclidine (PCP) treatment in the female rat produces robust cognitive defi cits and pathological changes that mimic those reported in schizophrenia (Neill et al. 2010, Pharmacol Ther. 128(3):419-32). The aim of this study was to investigate levels of NAA in the brain in the female rat following our sub-chronic PCP treatment regime. Methods: Adult female (n=16) hooded lister rats received sub-chronic PCP (2 mg/kg bi-daily, i.p, n=8) or vehicle (saline 0.9% bi-daily, i.p, n=8) for 7 days followed by a 7 day washout period. Six weeks later the rats were killed and brains removed. Brains regions were dissected in relation to Bregma coordinates [Frontal Cortex, +4.7 to +3.2mm; Striatum, +1.7 to -0.2mm; Dorsal Hippocampus -3.3 to -4.8mm; Ventral Hippocampus -4.8 to -6.3mm; Temporal Cortex -3.3 to -4.8mm mm. Tissue was homogenised, samples prepared and extracted with ISOLUTE SAX anion exchange columns, followed by HPLC analysis using UV detection. Data was analysed using One-way ANOVA. Results: Compared to vehicle, sub-chronic PCP treatment produced signifi cant reductions in NAA, in the frontal cortex (p<0.05) and ventral hippocampus (p<0.05), with no signifi cant changes in the striatum, dorsal hippocampus or temporal cortex. Discussion: These preliminary fi ndings demonstrate that sub-chronic PCP administration causes reductions in NAA in the frontal cortex and ventral hippocampus. This provides further evidence to suggest that sub-chronic PCP can mimic aspects of the neuronal pathology of schizophrenia and may provide a translational biomarker for assessing the effect of treatment on indicators of normal neuronal function. The relationship of the reductions in NAA in these regions to the cognitive defi cits reported in the sub-chronic PCP model remains to be determined. S Marsh is funded by the University of Bradford.

MF04

S(+)-KETAMINE AS A MODEL FOR PSYCHOSIS Kleinloog D, Centre for Human Drug Research (CHDR), Zernikedreef 10, 2333 CL Leiden, The Netherlands, 2333 CL, [email protected] Uit den Boogaard A (1), Klaassen E (1), Van Gerven J (1) (1) Centre for Human Drug Research (CHDR), Zernikedreef 10, 2333 CL Leiden, The Netherlands

Symptoms induced by the NMDA antagonist ketamine could constitute a model for psychosis and antipsychotic drug action. However, most studies did not measure pharmacokinetics and different outcome measures were used. The current study aimed to explore the optimal ketamine concentration and outcome measures for use within a psychosis model. Thirty-six healthy volunteers received intravenous infusions of S(+)-ketamine to obtain pseudo-steady state concentrations for two hours in a three-way cross-over design (placebo, low-dose, high-dose). Infusion rates were individualized by gender and weight and based on a pharmacokinetic model described by Sigtermans et al. (2009, Anesthesiology 111: 892-903). Target concentrations were selected based on simulations of dosing regimens used in the literature. Psychomimetic effects were measured using the Positive and Negative Syndrome Scale (PANSS), prepulse inhibition (PPI) and different visual analogue scales (VAS). General CNS effects were measured using CHDR’s NeuroCart, including eye movements, body sway, pupil size, adaptive tracking and serum cortisol and prolactin levels. Adverse drug effects were evaluated by describing adverse events and measuring vital signs and ECG. Results were analysed using an ANCOVA with a signifi cance level of 0.05. The study started with target concentrations of 180 and 360 ng/mL. After six subjects, the gradual development of adverse events led to a temporary halt and subsequent restart with lower target concentrations of 120 and 240 ng/mL. With these targets, a much better safety profi le was seen, although there were still many symptoms. During the 240 ng/mL target the infusion was terminated prematurely in 44% of the subjects. A robust psychomimetic effect was seen on all outcome measures, including PANSS (positive subscale: +43.7%, CI 34.4-53.7, p<0.0001 for 120 ng/mL and +70.5%, CI 59.0-82.8, p<0.0001 for 240 ng/mL) and PPI (+28.5, CI 10.6-46.4, p=0.0025 and +23.9, CI 4.6 - 43.3, p=0.0164). For most outcome measures a dose-dependent effect was seen, although the effect for PPI and smooth pursuit eye movements was similar for both targets, suggesting a maximum effect. For pupil size and adaptive tracking, only the higher target concentration showed a signifi cant effect. The ketamine- challenge was found to be a robust method to induce psychomimetic symptoms, that could be measured by the PANSS, prepulse inhibition and VAS. The response was larger and more consistent than found for a similar model using THC. The optimal target concentration for use in a psychosis model would be between 120 and 180 ng/ mL, based on a combination of tolerability and level of effect. The study was funded by the foundation CHDR and there are no confl icting interests to declare.

MF05

RISPERIDONE REVERSES SOME BEHAVIOURAL DEFICITS CAUSED BY COMBINED POST-NATAL PHENCYCLIDINE TREATMENT AND ISOLATION REARING POST-WEANING IN RATS

Gaskin PLR, School of Biomedical Sciences, Univ of Nottingham, Medical School, Queen’s Medical Centre Nottingham NG7 2UH [email protected] Fone KCF (1), Alexander SPH (1) School of Biomedical Sciences, Univ of Nottingham Medical School, Queen’s Medical Centre, Nottingham. NG2 7UH

The heterogeneous symptoms of schizophrenia make it diffi cult both to treat and to model in rodents. Previous work has shown that combining administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, phencyclidine (PCP), to rat pups on post natal days (PND) 7, 9 and 11, with subsequent rearing in social isolation from weaning produces several irreversible behavioural changes akin to changes in core symptoms seen in schizophrenia. This study assessed whether the antipsychotic drug, risperidone, could reverse these behavioural defi cits. Fifty male Lister-Hooded rat pups were administered PCP (10mg/kg, s.c.) or saline control on PND 7, 9 and 11, and subsequently weaned on PND 23 and housed either alone (isolation) or in groups of 3/4. Five weeks post-weaning rats were treated with either risperidone (0.1 or 0.2mg/kg i.p.) or vehicle control, before being monitored in a battery of behavioural tests to assess their locomotor activity (LMA), novel object discrimination (NOD), prepulse inhibition (PPI) of acoustic startle, and a conditioned emotional response (CER). Combined isolation/PCP (IP) treatment tended to elevate locomotor activity, particularly in the fi rst 20 minutes on the test, which appeared to be reversed by risperidone (0.1mg/kg). Locomotion was signifi cantly decreased in both control (GV) and IP groups receiving the highest dose of risperidone [p=0.0009 effect of treatment 1way ANOVA, p<0.05 for 0.1 and 0.2mg/kg Bonferroni post-hoc tests]. During the NOD test, GV-V rats discriminated the novel and familiar objects [p<0.001, Bonferroni post-hoc test following 2way ANOVA], but rats in the IP-V group did not. This effect was not reversed by risperidone treatment at either 0.1 or 0.2mg/kg. 0.2mg/kg risperidone treatment caused a signifi cant elevation in PPI in the IP group at 76 [p<0.05] and 80dB [p<0.01] prepulse levels. In the CER test IP rats showed signifi cantly decreased freezing at 24 and 48 hours post-conditioning, and following exposure to the conditioned stimulus [p<0.001]. Freezing was signifi cantly increased in the IP-Risp0.2 group following the conditioned stimulus [p<0.05 Boferroni post-hoc following 2way ANOVA]. The antipsychotic drug, risperidone, was able to reverse behavioural alterations including hyperlocomotion, decreased PPI, and impaired fear- motivated memory, caused by combined isolation rearing and post-natal PCP treatment. These results validate the use of isolation-PCP combination as a putative model of schizophrenia, and suggest it may help identify new compounds with potential for use as adjunct therapies for schizophrenia. This work was funded by the BBSRC ABSTRACTS A37

MF06

EFFECTS OF CHRONIC ANTIPSYCHOTIC DRUG TREATMENT ON CELL NUMBERS IN THE FRONTAL CORTEX OF MALE RATS Vernon AC, Psychosis Studies, Inst of Psychiatry, Kings College London, First Floor, The James Black Centre, 125 Coldharbour Lane, London, UK SE5 9NU anthony. [email protected] Chege W(1), Natesan S(1), Modo M(2), Cooper JD(2), Williams SCR(3), Kapur S(1). (1) Dept. Psychosis Studies, Inst of Psychiatry, Box PO 63, De Crespigny Park, Denmark Hill, London SE5 8AF (2) Dept. Neuroscience, Inst of Psychiatry, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU (3) Dept. Neuroimaging, Inst of Psychiatry Box PO 89, De Crespigny Park, Denmark Hill, London SE5 8AF

Neuropathological and neuroimaging studies suggest reduced gray matter volume of the cerebral cortex in schizophrenia. However, it is unclear to what degree this is due to illness or effects of antipsychotic medication. Indeed, we have recently demonstrated that chronic haloperidol treatment decreases neocortical volume by approximately 8-12% in rats at clinically relevant doses (Vernon et al., 2011, Biol Psychiatry 69(10): 936-44), which is reversible on drug withdrawal (Vernon et al., 2012 Biol Psychiatry http://dx.doi.org/10.1016/j.biopsych.2011.12.004). Consequently, in this study we sought to link volumetric differences identifi ed by imaging with changes at the cellular level. Haloperidol (HAL, 2 mg/kg/day), or vehicle (β-hydroxypropylcyclodextrin, 20% w/v, acidifi ed by ascorbic acid, to pH 6) (n=8 per group) was continuously administered to rats subcutaneously via osmotic mini-pumps for a total of 8 weeks. A separate group of animals received HAL or vehicle for 8 weeks, followed by 8 weeks of drug withdrawal. Upon completion of drug treatment or withdrawal, animals were sacrifi ced by terminal anaesthesia, perfused and brain tissue removed and processed histologically to produce Nissl stained coronal sections. The volume (cavalieri probe) and total number of neurons (optical fractionator) were then assessed in distinct cortical sub-fi elds post-mortem using unbiased stereology blinded to treatment group. Statistics were performed using SPSS 17.0 software. Chronic HAL- treatment resulted in an 8.62% reduction in the volume of the anterior cingulate cortex (ACC) (p<0.01) compared to vehicle-controls, which was reversed following drug withdrawal. No signifi cant volume changes were observed in the primary motor, somatosensory or visual cortices in HAL-treated animals compared to vehicle. Estimates of total neuron number in ACC gray matter in chronic HAL-treated animals (8 weeks) revealed no signifi cant changes in neuron number but a 14.79% higher neuron density (p<0.01). Chronic HAL treatment results in a signifi cant reduction of the volume of the rat ACC, associated with increased neuronal density, suggestive of reduced neuropil volume, most likely due to altered/reduced dendritic arborisation. Further analysis is currently underway to confi rm this and elucidate the effects following drug withdrawal. These data raise the possibility that volume changes in schizophrenia subjects might be due, at least in part, to antipsychotic medication effects. Furthermore, these fi ndings highlight the utility of this pre-clinical model system to investigate the neurobiology underlying antipsychotic drug induced changes on brain structure, linking neuroimaging to neuropathology. Acknowledgments: This research is supported by a Medical Research Council project grant awarded to S.Kapur.

MF07

DIFFERENT MOLECULAR PATHWAYS MEDIATING METABOLIC ABNORMALITIES OF FIRST- AND SECOND-GENERATION ANTIPSYCHOTICS Mondelli V, Psychological Medicine, Inst of Psychiatry, King’s College London, 125 Coldharbour Lane, London SE5 9NU, [email protected] Anacker C(1), Cattaneo A(1), Vernon A(1), Natesan S(1), Modo M(1), Dazzan P(1), Kapur S(1), Pariante CM(1) (1) Inst of Psychiatry, King’s College London, London, UK

Introduction: The increased prevalence of metabolic abnormalities, such as obesity and diabetes, in schizophrenia is partly attributed to antipsychotic treatment, in particular to second-generation antipsychotics. However, the pathogenesis of antipsychotic-induced disturbances of glucose homeostasis is still unclear. The aim of the study was to investigate the effects of both a fi rst-generation antipsychotic (haloperidol) and a second-generation antipsychotic (olanzapine) on visceral fat deposition and on critical nodes of insulin signalling pathway. Methods: We studied 24 male Sprague-Dawley rats. Eight rats were treated with vehicle, eight with haloperidol (2 mg/kg/ day) and eight with olanzapine (10 mg/kg/day). Vehicle, haloperidol and olanzapine were administered using osmotic minipumps for 8 weeks (approximately 5 human years). We assessed weight and used Magnetic Resonance Imaging to measure intra-abdominal fat at the end of the treatment. We run western blot analyses on samples of liver tissue to investigate insulin signalling pathway (protein levels of IRS-2, GSK3-alpha, GSK3-beta, GSK3-alpha-ser21, GSK3-beta-ser9). Results are presented as mean±SEM. Results: The haloperidol group showed higher percentage of visceral fat (%visceral fat 32.3±1.3) when both compared with vehicle group (23.0±2.6; p=0.004) and with olanzapine group (21.6±2.1; p=0.002); while there was no difference between the olanzapine and the vehicle group (p=0.7). The olanzapine group showed signifi cantly reduced IRS2 protein levels (p=0.01) and increased phosphorylation of GSK3-beta (p=0.02), and a trend for reduced phosphorylation of GSK3- alpha (p=0.1). No signifi cant difference was found in the expression of the investigated proteins between the haloperidol and the vehicle group. Conclusions: The effect of olanzapine in decreasing levels of IRS2 and phosphorylation of GSK3-alpha supports a direct effect of this drug on critical nodes of the insulin signalling pathway that could lead to insulin resistance. The effect of olanzapine on insulin pathway appears to be independent from an effect on fat deposition, as this group did not differ from the vehicle group for percentage of visceral fat. Interestingly, haloperidol appears to infl uence fat deposition but does not infl uence expression of proteins involved in the insulin signalling pathway in the liver tissue. These fi ndings support the presence of different molecular pathways mediating the metabolic side effects of fi rst- and second-generation antipsychotics. Acknowledgments: This research has been supported by the SLaM NHS Foundation Trust & Institute of Psychiatry NIHR Biomedical Research Centre for Mental Health; a ECNP Young Scientist Award and a Starter Grant for Clinical Lecturers from the Academy of Medical Sciences to V. Mondelli.

MF08

THE EFFECTS OF STRESS AND ITS BIOLOGICAL MEDIATORS ON HIPPOCAMPAL VOLUME IN FIRST-EPISODE PSYCHOSIS Mondelli V, Psychological Medicine, Inst of Psychiatry, 125 Coldharbour Lane, London SE5 9NU [email protected]

Background: Previous studies have reported an association between childhood and adulthood stressful events and the onset/relapse of psychosis. However, the mechanisms behind this association are still unclear. Individuals with psychosis show brain volume changes at the onset and during the transition to psychosis, suggesting a critical role of neuroplasticity in the development of this illness. The aims of the study were to investigate 1) the effects of stress on brain-derived neurotrophic factor (BDNF), one of the main neurotrophic factors, and 2) the association of BDNF and biological markers of the stress response (cytokine and cortisol) on hippocampal volume in individuals with fi rst-episode psychosis. Methods: BDNF, interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha messenger RNA levels were measured in the leukocytes of 49 fi rst-episode psychosis patients and 30 healthy controls. In the same subjects we measured salivary cortisol levels at 6 time points during the day and collected information about psychosocial stressors (number of childhood traumas, number of recent stressors, and perceived stress). Finally hippocampal volume was measured using brain magnetic resonance imaging in a subsample of 19 patients. Results: Patients had reduced BDNF levels when compared with controls (effect size, d=1.3, p<0.001). Stress, both during childhood and in adulthood, contributes to decreased levels of BDNF at the onset of psychosis, possibly through an infl ammation mediated pathway (adjusted R2=0.23, p=0.009). The same patients also presented increased levels of the infl ammatory markers interleukin-6 (IL-6; d=1.1; p<0.001) and TNF-alpha (d=1.7, p<0.001). Interestingly, low levels of BDNF, increased levels of IL-6 and increased levels of cortisol all signifi cantly and independently predicted a smaller left hippocampal volume in individuals with fi rst-episode psychosis (adjusted R2=0.71, p<0.001). Conclusions: These fi ndings suggest that biological abnormalities triggered by stress contribute to brain structure abnormalities at the onset of psychosis. Targeting biological pathways involved in the stress response might help to prevent development of psychosis and improve clinical outcome of patients with psychosis. In the medical setting, this could be potentially achieved both with the use of medications targeting biological pathways involved in the stress response or with psychological interventions aimed at decreasing levels of stress in these individuals. Acknowledgments: This research has been supported by the SLaM NHS Foundation Trust & Institute of Psychiatry NIHR Biomedical Research Centre for Mental Health; an ECNP Young Scientist Award and a Starter Grant for Clinical Lecturers from the Academy of Medical Sciences to V. Mondelli VALERIA MONDELLI WAS AWARDED THE 2012 BAP/ CAMBRIDGE COGNITION AWARD A38 ABSTRACTS

MF09

THE EFFECTS OF HALOPERIDOL AND ARIPIPRAZOLE ON REWARD TASK PERFORMANCE IN HEALTHY VOLUNTEERS Handley R, Psychosis Studies, Inst of Psychiatry, Kings College London, PO63 De Crespigny Park London SE5 8AF [email protected] Rubia K(1) Mondelli V (1) Taylor H(1) Reis Marques T(1) Reinders AATS(1) O’Daly O(1) Chaddock C(1) McGuire P(1) Murray R(1) Kapur S(1) Williams S(1) Pariante C(1) Dazzan P(1) 1) Inst of Psychiatry, De Crespigny Park, London, UK SE5 8AF

Processing in the reward systems is notably impaired in schizophrenia and reward dysfunction has been attributed to a variety of symptoms. Dopamine function is closely linked with reward processing and antipsychotic drugs have a marked impact on the dopamine system. However, the effects of antipsychotics on reward processing in the absence of psychopathology remains unclear. This study investigated the effects of aripiprazole, an atypical antipsychotic with partial agonism activity on D2 and 5-HT1A receptors, and haloperidol on behavioural performance during a reward paradigm, in the same healthy individuals. Haloperidol (3mg) and aripiprazole (10mg) were administered to 17 healthy Caucasian males (mean age: 23, SD:4.8yrs) in a randomized, double-blind cross-over placebo controlled design. Volunteers had no past psychiatric history, recent recreational drug or tobacco use. Reward, non reward and non target letters were visually presented, following instruction to move a joystick in response to target letters (X/O). Self reported mood was recorded at 5 time points across the day. Repeated measures ANOVAS and ANCOVAS were used to explore intervention effects on behavioural cognition, controlling for mood. Number of correctly identifi ed (NC) rewarded and non rewarded stimuli and reaction times (RTNC) were analysed and corrected for family wise error. Antipsychotics were compared with one another and placebo. Compared with placebo, NC was impaired after aripiprazole, signifi cantly in the non rewarded condition (p=.002), and at trend level on the rewarded condition (p=.059). After controlling for mood, the trend in rewarded NC impairment was no longer evident. In contrast, for non rewarded stimuli, NC remained impaired after aripiprazole relative to haloperidol (p=.04). RTNC was also signifi cantly slower following aripiprazole compared with placebo in both the rewarded (p<.001) and non rewarded conditions (p=.001), even after controlling for mood. In addition, in the non rewarded condition, the same pattern was evident relative to haloperidol (p=.05). Haloperidol was not signifi cantly associated with any change in reward task performance compared with placebo. In summary, reward processing appears impaired following aripiprazole and these effects seem independent of drug- induced mood changes, suggesting that a direct neurochemical alteration may underpin these behavioural effects. In contrast, reward processing and mood seem not affected by haloperidol. These results support the notion that neurotransmitter systems other than dopamine may be involved in reward processing. Further investigation is required to understand the neural networks underpinning these alterations. Acknowledgments The study is supported by the American Psychiatric Institute for Research and Education (APIRE) and the NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King’s College London

MF10

THE 5-HT1A PROMOTER POLYMORPHISM AND ANTIPSYCHOTIC TREATMENT RESPONSE - PHARMACOGENETIC ASSOCIATION WITH THE FIVE SYNDROME DIMENSIONS IN PANSS Tang H, Neuropsychiatric Dept, Neuropsychiatric Res Inst, Southeast Univ Medical School, No 87 Dingjiaqiao Road. Nanjing, Jiangsu Province P.R.China 210009 [email protected] Arranz B(2), San L(2) , Reynolds GP(1) 1 Biomedical Res Centre, Sheffi eld Hallam Univ, Sheffi eld; 2 Hospital and Parc Sanitari Sant Joan de Deu, CIBERSAM, Barcelona, Spain

Association of the -1019C/G polymorphism of the 5-HT1A receptor gene (HTR1A) with negative symptom response to antipsychotic treatment in fi rst episode psychosis (Reynolds et al, 2006 Am J Psych 163, 1826-1829) has been replicated in several populations. This association is also seen in changes in general psychopathology but not in positive symptoms. Some of these fi ndings will refl ect an association with depressive symptom response, which was also observed in the original paper. While PANSS items are classically divided into three symptom clusters, factor analysis often identifi es fi ve dimensions of symptoms. To obtain a better understanding of the specifi city of the association of the HTR1A polymorphism with symptoms and their response to treatment in psychosis, we reanalysed data from the original study for pharmacogenetic association with these fi ve symptom clusters. PANSS symptom items of 75 fi rst-episode drug-naïve patients were divided into fi ve symptom factors according to Mass et al, 2000 Schiz Bull 26, 167-177. Associationswith HTR1A genotype of each factor’s baseline score and their changes after 3 months’ treatment (n=63) were determined by ANOVA; baseline score was also used as a covariate in determining association with treatment response. A signifi cant association of genotype was observed with the negative symptom factor (p<0.01) at baseline, but not with other factors. As association with symptom response to treatment was observed in the negative (p<0.001) and depression (p=0.001) syndromes; in each case the CC genotype was associated with greater symptom response than G allele carriers. There was no association with response in positive, excitement and cognitive syndromes. Inspection of individual PANSS items showed signifi cant effects of treatment only on items N1 and N2 within the negative syndrome. These results demonstrate the specifi city of the original fi ndings in the association of the HTR1A polymorphism with response of negative symptoms and depression to treatment of fi rst-episode patients with antipsychotic drugs. This association within the negative syndrome may be restricted to a subgroup of negative symptoms. It is notable that there was no association with the cognitive syndrome; these fi ndings indicate the circumscribed extent of the infl uenceof the 5-HT1A receptor in antipsychotic action on the symptoms of schizophrenia. ABSTRACTS A39

MF11

CHARACTERISTICS OF PATIENTS PRESCRIBED QUETIAPINE INSTANT RELEASE (IR) AND EXTENDED RELEASE (XL) FORMULATIONS IN A PRIMARY CARE DATABASE (GPRD) Rigney U, AstraZeneca UK, Horizon Place, 600 Capability Green, Luton LU1 3LU [email protected] Emmas C, Blak BT, Lichfi eld J, Wootton P – address as presenter

Introduction: The antipsychotic medication quetiapine exists as instant release (IR) and extended release (XL) formulations with quetiapine IR UK license for bipolar disorder and schizophrenia (twice daily, except bipolar depression once daily). Quetiapine XL has bipolar, schizophrenia and major depressive disorder (MDD) licence (all once daily). There is emerging evidence that these formulations are prescribed differently. The study objectives were to examine characteristics of patients prescribed quetiapine IR and XL in UK primary care within common licensed diseases and to describe drug utilisation patterns for these cohorts. Methods: Within the longitudinal observational UK General Practice Research Database, patients≥18 years old with a fi rst ever (index) quetiapine IR or XL between 01/01/08-31/12/10 were selected. Follow-up was 6 months. Demographics; morbidity history; prescribing on/24 months prior index and during follow-up, and mental health hospitalisations within 24 months prior index were derived. Proportion of Days Covered (PDC) was days coverage of prescribed index medication during follow-up divided by total follow-up days (182). Dosage and PDC estimations were restricted to prescriptions including complete daily dose information. Descriptive statistics were derived by IR/XL cohort and descriptively compared. Results: There were 7,404 IR patients of whom 1,199 (16.2%) had bipolar/schizophrenia indications recorded and 3,204 XL patients of whom 2,097 (65.4%) had bipolar/schizophrenia/MDD recorded. 1,169 (36.5%) XL patients had bipolar/schizophrenia indications recorded. Within schizophrenic IR patients, follow-up daily IR mean and modal dose were 214.1mg/day (95%CI:197.0-231.2,n=462) and 200mg, respectively. Within schizophrenic XL patients, follow-up daily XL mean and modal dose were 376.9mg/day (95%CI:353.4-400.3,n=465) and 600mg, respectively. The mean age was 48.9 years (95%CI:48.0-49.8) and 45.9 years (95%CI:45.1-46.7) for bipolar/schizophrenia IR and XL patients respectively. Of bipolar/schizophrenia IR patients, 9.8% received quetiapine XL prior to index. Of bipolar/schizophrenia XL patients, 51.7% received quetiapine IR prior. 8.4% and 9.3% of bipolar/schizophrenia IR and XL patients respectively had a prior hospitalisation. PDC was 63.5% (95%CI:61.3-65.6,n=1,024) and 67.9% (95%CI:65.9-69.9,n=1,058) in bipolar/schizophrenia IR and XL patients respectively. Conclusions: A larger proportion of the XL patients compared to IR patients had licensed diseases recorded. Descriptively compared to quetiapine IR patients, XL patients were prescribed higher quetiapine dose, were slightly younger and more had prior quetiapine (IR) prescriptions. The observation of more XL patients with prior hospitalisations and higher quetiapine dosage may suggest that XL is prescribed for more severe patients. The unadjusted PDC was higher among XL patients indicating patients on XL were supplied more days of medication compared to IR patients. Source of fi nancial sponsorship: AstraZeneca sponsored this study.

MF12

PSYCHIATRISTS’ PERSPECTIVES REGARDING ANTIPSYCHOTICS: DOSE CHOICE AND PLASMA LEVEL THERAPEUTIC DRUG MONITORING Best-Shaw (1), Nagar J (2), David AS (1), Rose D (1), Patel MX (1). 1. Dept of Psychosis Studies, Inst of Psychiatry, King’s College London, Box 68, DeCrespigny Park, London SE5 8AF [email protected] 2. North London Hub, Mental Health Research Network, London

Introduction: The method by which a psychiatrist chooses the dose of antipsychotic for an individual patient is somewhat arbitrary. We aimed to explore how psychiatrists currently titrate antipsychotic dose, and choose the optimum dose for patients with acute psychosis, as well as to investigate psychiatrists’ perspectives on drug plasma level therapeutic monitoring (TDM) for antipsychotics. Method: This was a cross-sectional questionnaire quantitative study of consultant psychiatrists. Focus groups for clinicians and service users were fi rst conducted to explore possible themes for the questionnaire. These included: factors infl uencing dose preference and choice, perspectives regarding dose titration including during drug switching, perspectives on individualised dosing, potential benefi ts and negative aspects of TDM use, potential barriers to TDM use and also impact of TDM on changing clinical practice. Based on fi ndings from the focus groups and the literature, item statements for a new questionnaire were developed. Questionnaire data collection was subsequently conducted in 04/2011-03/2012 in 4 mental heath NHS Trusts in London, UK. Preliminary fi ndings are reported. Results: For 100 consultant psychiatrists, antipsychotic dose titration methods for acute relapse of schizophrenia included: start at a low dose and gradually increase over 2-4 weeks until a “target” dose is reached (73%); continue increasing the dose until the patient’s symptoms improve (67%). Most agreed that when choosing an optimum dose, they had a usual dosing regimen for patients presenting in a similar way (81%), or that choice was infl uenced by their perspectives on the equivalent doses of two antipsychotics (71%) or the individual patient’s stated dose preference (63%). An adequate trial of an antipsychotic was considered to be 4-6 weeks (67%), <4 weeks (9%), >6 weeks (23%). Almost all (84%) agreed that avoidance of total discontinuation of all antipsychotic treatment by patient was a reason why they switched between two antipsychotics, and just under half (44%) believed there is no maximum to the number of times it is acceptable to switch a patient’s antipsychotic in one year. 83% of clinicians agree that they would use TDM for antipsychotics if it were readily available. Conclusions: This study outlines the current state-of-play regarding clinician perspectives and knowledge regarding antipsychotic prescribing, optimum dose choice, individualised prescribing and use of TDM. If readily available, monitoring plasma concentrations may improve choice of dose, as there is wide inter-individual variation in terms of bioavailability of certain antipsychotics. This study was funded by an NIHR Clinician Scientist award for Dr Maxine Patel.

MF13

COMMUNITY TREATMENT ORDERS AND ANTIPSYCHOTIC FORMULATIONS: NATURALISTIC OUTCOMES Patel MX, Dept of Psychosis Studies Inst of Psychiatry, King’s College London, box 68 16 DeCrespigny Park London, SE5 8AF, [email protected] Matonhodze J (2), Baig MK (3), Taylor D (3), Szmukler G (1), David AS (1) (1) Inst of Psychiatry, King’s College London, DeCrespigny Park, London SE5 8AF, UK; (2) Univ Of Greenwich, Avery Hill Campus, Eltham, London SE9 2UG; (3) South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AZ

Introduction: Since their introduction in 2008, and despite a weak evidence-base, community treatment orders (CTOs) have been commonly used in England and Wales. CTOs are perhaps most commonly initiated in order to compel the patient to continue taking their medication in the community. We aimed to evaluate the naturalistic outcomes of CTOs in terms of discontinuation versus renewal as well as hospital admissions, according to antipsychotic formulation prescribed. Method: A cohort study with one year follow-up and with prospective consecutive sampling was conducted for all patients whose CTO was registered in a large mental health Trust. Only the fi rst CTO for each patient was included. Measures included: sociodemographic and clinical variables, psychotropic medication, CTO conditions,and outcomes and hospitalisation. Comparison groups were determined by antipsychotic formulation at CTO onset and comprised long-acting injection (LAI) versus oral only.This cohort was identifi ed in the fi rst year of CTO legislation in England and Wales. Results: 195 patients were sampled (mean age 40.6 years, 65% male) and 6 were lost to follow up. For the majority of the remaining 189, the CTO ceased within one year and this was either due to revocation (22%), discharge by a clinician (28%) or by being allowed to lapse (20%). Ninety-two (48.7%) patients had their CTO renewed at 6 months, and 56 (29.6%) were renewed for a second time at 12 months. Time to CTO cessation was signifi cantly longer for LAI than for oral (median 251 days vs 182 days, Kaplan-Meier Log rank-Mantel-Cox X2=4.69, p=0.030). 54/189 (28.6%) experienced at least one admission to hospital whilst their CTO was active and within the 12 month follow-up period. The mean time to fi rst admission was 147.1 days and did not differ according to antipsychotic formulation. Conclusions: CTO duration was longer for those prescribed an antipsychotic LAI (vs oral) at the time that the CTO was fi rst initiated although time to fi rst admission and number of admissions experienced did not differ. CTOs not only compel treatment but bind services to the patient, resulting in more intensive follow up. Whether enhanced treatment, enabled by the CTO, can translate into improved clinical outcomes is yet to be determined. Source of funding: Own Account. A40 ABSTRACTS

MG01

HARNESSING DRUG-USER EXPERIENCES TO EVALUATE THE VERISIMILITUDE OF PHARMACOLOGICAL MODELS OF PSYCHIATRIC ILLNESS Brugger S, St George’s, Univ of London, Cranmer Terrace London SW17 0RE [email protected] Carhart-Harris R(1), Nutt D(1), Stone JM(1) (1) Div of Experimental Medicine, Imperial College London, Du Cane Rd, London W12 0NN

The administration of psychotomimetic drugs to healthy volunteers is currently a popular paradigm in the modelling of psychiatric illness (Corlett et al. 2009, Psychopharmacology 206:515-530). However, this approach has been criticised and it remains unclear which drugs most closely model each disorder. We conducted a 2-phase internet-based survey of polydrug users and mental health professionals in order to clarify this issue. In phase 1, mental health professionals were presented with a number of statements summarising psychiatric symptoms, and were instructed to select to which of 9 states (mania, anxiety, post-traumatic stress disorder, depression, formal thought disorder, positive, negative and cognitive psychotic symptoms, mystical/spiritual experiences) each most typically related. In phase-2, polydrug users rated the likelihood of experiencing each symptom following use of fi ve drugs – high-potency cannabis, alcohol, ketamine, psilocybe mushrooms and amphetamine. A network model instantiating the questionnaire results was constructed, with nodes representing symptoms and endogenous/drug-induced states linked via weighted edges. The ‘fl ow’ between drug/endogenous-state nodes through this network – i.e. the extent of symptomatic overlap – was taken as a measure of the verisimilitude of the drug model, with signifi cance testing via Monte Carlo methods (99,999 permutations). Phase-1 was completed by 63 respondents and phase-2 by 224 respondents. Mania was best modelled by the acute effects of amphetamine (symptomatic overlap=2.67, verisimilitude=58%, p=0.004), followed by alcohol (2.62, 57%, p=0.005). The best models of anxiety disorder were high-potency cannabis (1.88, 54%, p=0.06) and the sub-acute ‘low’ following amphetamine use (1.92, 55%, p=0.05); the latter also constituted the best model of depression (2.25, 45%, p=0.01) and negative psychotic symptoms (1.36, 100%, p=0.0005). Negative syndrome was also modelled by ketamine (1.25, 91%, p=0.01) and the sub-acute low following alcohol (1.30, 95%, p=0.005). Formal thought disorder and cognitive symptoms in psychosis were also most closely modelled by ketamine (2.02, 72%, p=0.02; 1.05, 100%; p=0.005). Psilocybin most signifi cantly mimicked spiritual/mystical experiences (2.02, 84%, p=0.0005). Positive psychotic symptoms were not signifi cantly reproduced by any drug. These results suggest that drug-user experiences ‘in the community’ do not fully map onto established theories about pharmacological modelling of psychiatric illness. In particular, we failed to fi nd evidence for signifi cant correspondence between the phenomenology of positive symptoms and amphetamine, ketamine or high-potency cannabis. However, other facets of psychosis are reproduced well, particularly by ketamine. Additionally, the sub-acute ‘low’ following amphetamine use may be a useful pharmacological model warranting further investigation. This study received funding from the Independent Scientifi c Committee on Drugs.

MG02

FUTURE THINKING ABILITIES OF ILLICIT DRUG USERS Mercuri K, Psychology, Australian Catholic Univ, Level 2, 115 Victoria Parade, North Fitzroy, Victoria, Australia 3053, [email protected] Terrett G (1), Rendell PG (1) (1) Australian Catholic Univ, School of Psychology, Level 2, 115 Victoria Parade, North Fitzroy, Victoria, Australia

Future Thinking (FT) involves the projection of the self into the future to pre-experience an event. Recent infl uential neuroscience reviews suggest future thinking is critical for humans in daily living, and impacts signifi cantly on the ability to plan and make decisions. FT relies on similar neural mechanisms to episodic memory and has been linked to various executive functions (Schacter et al, 2008, Annals of the New York Academy of Sciences, 1124, 39-60). However emerging studies of FT suggest that imagining the future requires more demanding cognitive processes than past remembering. This study will focus on FT ability in short term cannabis users and long term heroin users. Both groups have been shown to display defi cits in episodic memory, response inhibition and decision making (Fernández-Serrano et al, 2011, Neuroscience and Biobehavioral Reviews, 35, 377-406), which suggests FT may be compromised in these groups. Cannabis users often display modest defi cits in these areas in comparison to healthy controls; whereas heroin dependent users tend to exhibit more pronounced cognitive defi ciencies. This suggests that these groups may show different levels of diffi culty with FT. To our knowledge, there has been no empirical research on FT ability and substance use with the exception of two recent studies showing the use of FT as a memory enhancement strategy reduced prospective memory defi cits associated with alcohol intoxication (Paraskevaides et al, 2010, Psychopharmacology, 208, 301-308). Experiment 1 tested 23 short term cannabis users and 45 healthy controls with no history of illicit substance use recruited from the general community. Forty precent of the cannabis sample were novel users, indicating lifetime duration of use of less than 1 year. Groups were matched on age and crystallised intelligence. The groups did not differ (p > .125) on any of the key measures of executive functioning (Trail Making Test, Hayling Sentence Completion, Verbal Fluency), emotion processing (Ekman Pictures of Facial- Affect), theory of mind (Mind in the Eyes test) and FT (Autobiographical Interview). Preliminary results suggest that this drug using group does not demonstrate defi cits in FT ability. Experiment 2 replicated Experiment 1 but involved 20 heroin dependent users engaged in pharmacological substitution for their dependence; and 20 controls matched on age, education and crystallised intelligence. Differences on executive functioning, emotions processing, theory of mind and FT are predicted given large cognitive defi cits reported with this substance user population. I am a recipient of an Australian Postgraduate Award Scholarship, and have received small grants from the Faculty of Arts and Sciences at the Australian Catholic University. ABSTRACTS A41

MG03

IN VIVO BRAIN DOPAMINE SYNTHESIS CAPACITY AND CANNABIS RELATED PSYCHOTIC SYMPTOMS: AN [18F]-DOPA POSITRON EMISSION TOMOGRAPHY STUDY IN CANNABIS USERS Bloomfi eld MAP, Psychiatric Imaging Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road London W12 0NN michael. bloomfi [email protected] Morgan CJA(3), Egerton A (1,2), Kapur S (2), Curran HV (3), Howes OD (1,2) (1)MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, Du Cane Road, London W12 0NN (2) Inst of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF (3) UCL Clinical Psychopharmacology Unit, 1-19 Torrington Place, London WC1E 7HB

INTRODUCTION: Cannabis is the most widely used illicit drug in the world and users are at increased risk of schizophrenia. It remains unknown whether cannabis use is associated with the striatal dopaminergic dysfunction seen in other addictions or schizophrenic psychosis (Fusar-Poli & Meyer-Lindenberg 2012. Schizophr Bull. doi: 10.1093/schbul/sbr180). We addressed this by comparing dopamine synthesis capacity in young regular cannabis users who experienced a transient increase in psychotic-like symptoms when they consumed their own cannabis with non-user controls. METHODS: Striatal dopamine synthesis capacity was assessed using [18F]6- fl uoro-l-DOPA (F-DOPA) positron emission tomography in 19 regular cannabis users [mean (SD) age = 20.8(1.7)] compared to 19 healthy control subjects [mean (SD) age = 22.3(2.8)], matched for age and sex. The cannabis users had reported experiencing a transient increase in psychotic-like experiences when they consumed their own cannabis (Morgan et al. 2012 Psychological Medicine. 42, 391-400), but did not meet the diagnostic threshold for a psychotic disorder and were not acutely intoxicated with cannabis at the time of scanning. Presynaptic dopamine synthesis capacity was indexed as the F-DOPA infl ux rate in regions-of-interest defi ned in the striatum and its functional subdivisions (Martinez et al. 2003, J Cereb Blood Flow Metab; 23:285–300), relative to the cerebellar reference region (Kicer). RESULTS: Signifi cant group differences were observed. Compared to controls, cannabis users had reduced dopamine synthesis capacity in the striatum (t(36)=2.54, p<0.05) and its associative (t(36)=2.54, p<0.05) and limbic subdivisions (t(36)=2.23, p<0.05) (effect sizes=0.8). The fi nding of reduced striatal Kicer in cannabis users remained signifi cant after co- varying for other drug use (F(1,37)=4.648, p<0.05). A voxel-based analysis confi rmed reduced Kicer in the user group relative to non-user controls with its focus in the right putamen (p<0.05, corrected for multiple comparisons using the family-wise error rate). In cannabis users, there were signifi cant correlations between reduction of striatal dopamine synthesis capacity and severity of cannabis use (r=0.77, p<0.001) and age of onset of cannabis use (r=0.51, p<0.05), but not with induction of psychotic- like symptoms following consumption of the drug (r=0.32, p=0.19). CONCLUSIONS: These fi ndings suggest that regular cannabis use is associated with presynaptic dopaminergic dysfunction in individuals who experience transient psychotic-like symptoms when acutely intoxicated with the drug, and that this is correlated with the degree of cannabis use. Further research is needed to investigate the neurobiological mechanisms underlying the associations between cannabis use, cannabis dependence and the development of an enduring psychotic illness. This study was funded by the Medical Research Council.

MG04

EXECUTIVE FUNCTION DEFICITS IN ABSTINENT CANNABIS USERS: THE EFFECT OF THE AGE OF ONSET Reynolds J, Psychology, Sociology and Politics, Sheffi eld Hallam Univ, Oak Lodge Collegiate Crescent, Sheffi eld S10 2BP, [email protected] Mchale S(1), Barker L(1), Reidy L(1), Dalton C(4) (1) Southbourne, Sheffi eld Hallam Univ, Collegiate Crescent, Sheffi eld, S10 2BP (2) Biomedical Research Centre, Sheffi eld Hallam Univ, Howard Street, Sheffi eld S1 1WB

Defi cits associated with chronic cannabis use are well documented particularly in relation to the executive functions of abstract thought, inhibition, set switching and programming of complex motor tasks (Medina et al, 2007, Journal of International Neuropsychology, 13, 807-820). However, there is a dearth of research into long term effects of cannabis use on the developing brain. Recent morphological data show that frontal networks of the brain associated with executive functions have protracted development through adolescence to late adulthood that may confer vulnerability to the toxicity associated with prolonged drug use (Paus et al, 2008, Nature Reviews Neuroscience, 9, 947-957). The present study utilises a number of neuropsychological tasks to investigate whether there are differences in executive functions between a group who started using cannabis at an early age (≤15 ), a group who started using cannabis at a later age (>15), a tobacco using group and a control group. Participants were at least 3 days abstinent from cannabis use at time of testing. Recent drug use was determined using gas chromatography mass spectrometry. Preliminary results show evidence of early-onset-related executive defi cits across several neuropsychological tasks. The early group (p<.02) and late group (p<.05) both presented with defi cits on the switching condition of the Trail Making Task (Delis et al, 2001, New York, Pearson) compared with the control group. The early group also presented with defi cits on the contrast measure of the Grooved Pegboard Task (Mathews & Klove, 1964, Madison, WI, University of Wisconsin Medical School) when compared to the tobacco using group (p<.05) whereas the late group did not. The early group also showed multiple defi cits in performance across the Verbal Fluency Task (Delis et al, 2001, New York, Pearson) when compared with the late group, specifi c to the number of responses in the set switching phase (p<.05), the total percentage of errors made (p<.05) and the number of responses generated in the fi rst 15 seconds (p<.05). As these defi cits were found not to be due to total lifetime consumption of cannabis, the present study highlights the vulnerable nature of the developing brain. The present fi ndings suggest that processes including set switching, motor programming, working memory and declarative memory are impaired as a result of early cannabis use. Funding was provided by Sheffi eld Hallam University to compensate the participants for taking part in the experiment. Each participant received £10 worth of vouchers. A42 ABSTRACTS

MG05

FRONTAL BRAIN VOLUMES IN EARLY ADOLESCENCE DIFFERENTIALLY PREDICT THE DEVELOPMENT OF ALCOHOL-RELATED PROBLEMS AND CANNABIS USE AT AGE 16: A 4-YEAR LONGITUDINAL AND PROSPECTIVE COHORT STUDY Lubman DI, Turning Point Alcohol and Drug Centre, Eastern Health and Monash Univ, 54-62 Gertrude Street, Fitzroy, Victoria, Australia 3065 [email protected] Cheetham A (1), Whittle S (1,2), Simmons J (1), Yücel M (2), Allen NB (1) (1) Orygen Youth Health Research Centre, Univ of Melbourne, 35 Poplar Road, Victoria 3052, Australia (2) Melbourne Neuropsychiatry Centre, Univ of Melbourne and Melbourne Health, 161 Barry Street, Victoria, 3053, Australia

Introduction: There is evidence that long-term, heavy use of alcohol and other substances is associated with alterations in regional brain volumes. Adolescence is a period of particular concern in this regard, given the adverse consequences associated with early use and the potential impact of substance exposure on the developing brain. However, while these changes are frequently attributed to the neurotoxic effects of prolonged use, it is possible that some abnormalities predate use and represent markers of vulnerability. To date, no prospective studies have examined whether structural brain abnormalities are present prior to the onset of use in adolescence. Methods: In two studies drawn from a community sample of 245 healthy adolescents (50.60% female), we examined whether individual differences in brain volume were associated with early use of alcohol and cannabis. Specifi cally, we examined whether adolescents who had (i) experienced alcohol-related problems and (ii) initiated cannabis use early (i.e., prior to age 17) showed premorbid structural abnormalities in the amygdala, hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Participants underwent structural magnetic resonance imaging at the baseline assessment (M age=12.6 years), and were assessed for alcohol-related problems and cannabis use at follow-up four years later (M age=16.5 years). Results: Of the fi nal sample of 121 adolescents (48.8% female) who completed these measures at both time points, 38 (31.4%) reported experiencing alcohol-related problems at the follow-up assessment, and 28 (23.1%) reported ever using cannabis. Using logistic regression, adolescents who reported experiencing alcohol-related problems at the follow-up assessment were found to have smaller baseline volumes of the left rostral paralimbic ACC (p =.001) and left dorsal paralimbic ACC (p =.002), compared to adolescents who reported drinking without experiencing problems. In contrast, adolescents who reported initiating cannabis use by the follow-up assessment were found to have smaller baseline volumes of the right lateral OFC (p =.029), compared to adolescents who had not initiated cannabis use by this time point. For both analyses, these results remained signifi cant even after controlling for lifetime use of other substances and substance use prior to the baseline assessment. Conclusions: These fi ndings suggest that structural abnormalities in the ACC and OFC may contribute to risk for problematic alcohol use and early cannabis exposure, respectively. These results have implications for understanding the neurobiological predictors of alcohol and cannabis use in adolescence, including potential differences in the antecedents of licit versus illicit substance use. The research was supported by grants from the Colonial Foundation, National Health and Medical Research Council and Australian Research Council.

MG06

AUTOMATIC ALCOHOL COGNITIONS IN HEAVY DRINKERS: STRONG APPETITIVE TENDENCIES, WEAK AVOIDANCE TENDENCIES, OR BOTH? Field M, Dept of Experimental Psychology, Univ of Liverpool, Eleanor Rathbone Bldg, Bedford Street South, Liverpool L69 7ZA mfi [email protected] Dickson J, Gullo M. Inst for Psychology Health and Society, Univ of Liverpool, L69 7ZA

INTRODUCTION: Heavy drinkers exhibit biased cognitive processing of alcohol-related cues in the form of attentional biases and automatic approach tendencies elicited by the cues. However due to ambiguities in existing methods, it is unclear if these results refl ect strong automatic appetitive responses, or weak automatic aversive responses, to the cues. METHODS: 108 heavy social drinkers included a battery of cognitive tests included modifi ed stimulus-response compatibility (SRC) tasks to assess automatic approach and avoidance tendencies evoked by alcohol cues, a modifi ed visual probe task to assess biases in rapid orienting and delayed disengagement of attention from alcohol-related cues, and an affective priming task to assess automatic affective reactions to alcohol-related words. RESULTS: On the modifi ed SRC tasks, alcohol-related cues evoked fast approach responses but not slow avoidance responses, relative to neutral cues; furthermore, these effects were only seen when participants were required to categorise the pictures on the basis of their alcohol-relatedness. On the modifi ed visual probe task, participants were slow to disengage their attention from alcohol-related cues, but were not faster to orient their attention to alcohol cues. Alcohol-related cues also had a general slowing effect on reaction times. On the affective priming task, alcohol-related primes slowed categorisation of negative targets, but did not speed categorisation of positive targets. There were no signifi cant correlations between any of the cognitive bias indices and individual differences in alcohol consumption or alcohol-related problems. CONCLUSIONS: These results clarify the nature of automatic processing biases in heavy drinkers as they confi rm that automatic approach tendencies elicited by the cues can be attributed to strong approach tendencies rather than weak avoidance tendencies, and that alcohol-related cues seem to inhibit processing of negative information without facilitating the processing of positive information. Studies which use the visual probe task should be mindful of general slowdown effects produced by the presence of alcohol-related cues when interpreting reaction time indices of attentional bias. Funded by a research grant from the Wellcome Trust.

MG07

RELATIONSHIP OF CYTOKINE CONCENTRATIONS WITH THE SEVERITY OF ALCOHOL HANGOVER SYMPTOMS van Seyen M, Div of Pharmacology, Utrecht Univ, Universiteitsweg 99, Utrecht, The Netherlands 3584CG [email protected] Van Seyen M, Cheung CW, Slot KA, Penning R, Olivier B, Verster JC Utrecht Univ, Div of Pharmacology, Universiteitsweg 99, 3584CG, Utrecht, The Netherlands

Introduction: Although the pathology of alcohol hangover is unclear, involvement of the immune system has been suggested. This study examined if cytokine concentrations can be related to the severity of alcohol hangover symptoms. Methods: In a naturalistic study, N=109 participants, completed an online survey the day after an evening of heavy drinking, and the day after another evening on which no alcohol was consumed. The survey included alcohol consumption questions, severity scoring of 21 common hangover symptoms and a 1-item overall hangover severity score (all ranging from 0-10). Saliva samples were collected to determine cytokine levels (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, TNF-α, IFN-γ). Participants were included in the data analyses if their estimated blood alcohol concentration (BAC) was ≥ 0.11%, and if they confi rmed having a hangover. Difference scores (hangover day – control day) were used in all statistical analyses. Results: Data from N=64 participants was included in the statistical analyses. These were 25 (39.1%) men and 39 (60.1%) women, mean (SD) age 21.4 (2.9) years old. Mean (SD) number of alcoholic consumptions on the evening before the hangover day was 11.1 (5.4). They reported an overall hangover severity score of 4.5 (2.2). Most frequently reported and most severe hangover symptoms were being tired, thirst, sleepiness and reduced appetite. During hangover, concentrations of most cytokines were signifi cantly decreased relative to the control day. Overall hangover severity correlated signifi cantly with CM-CSF (r = -0.31, p=0.08), IFN- γ (r = -0.30, p=0.02), and IL-4 (r = -0.28, p=0.03). Apathy, confusion, sensitivity to light, shivering, and feelings of guilt correlated signifi cantly to CM-CSF and IFN- γ, and a variable number of other cytokines. Regret, weakness, dizziness, and sweating correlated signifi cantly only to IL-8, whereas heart pounding and anxiety correlated signifi cantly only to IL-1β. The magnitude of signifi cant correlations was modest and ranged from r = -0.26 to r = -0.42. For headache, nausea, vomiting, sleepiness, being tired, clumsiness, concentration problems, thirst, depression, and reduced appetite no signifi cant correlations were found with cytokine levels. Conclusions: The day after an evening of heavy drinking, a modest suppression of both pro-infl ammatory and anti-infl ammatory cytokines was observed. Whereas some symptoms clearly relate to change in cytokine concentration, other common symptoms such as headache, thirst, and being tired do not correlate with cytokine concentrations. Acknowledgment: thi study was funded by Utrecht University ABSTRACTS A43

MG08

IN VIVO IMAGING OF CEREBRAL DOPAMINE D3 RECEPTORS IN ALCOHOLISM Erritzoe D, Neuropsychopharmacology Unit, Imperial College London, Burlington Danes Bldg 5th fl oor, Hammersmith Campus, 160 Du Cane Road, London W12 0NN [email protected] Tziortzi A(2,3), Bargiela D(1), Searle G(2), Gunn RN(2), Beaver JD(2), Waldman A(4), Nutt DJ(1), Bani M(5), Merlo-Pich E(5), Rabiner EA(2), Lingford-Hughes A(1) (1) Neuropsychopharmacology Unit, Centre for Pharmacology and Therapeutics, Imperial College London, London, UK (2) Clinical Imaging Centre, GlaxoSmithKline, London, UK (3) FMRIB centre, Dept of Clinical Neurology, Univ of Oxford, Oxford, UK (4) Dept of Imaging, Charing Cross Hospital, London, UK (5) CEDD for Neurosci, GlaxoSmithKline, Verona, Italy.

Background: Evidence from animal studies suggests a role for the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking (Heidbreder et al., CNS NeurolDisordDrugTargets. Nov2008;7(5):410-421), and selective blockade of DRD3 in rat reduces ethanol preference, consumption (Thanos et al. PharmacolBiochemBehav. May2005;81(1):190-197), and cue-induced reinstatement of alcohol self-administration (Vengeliene et al. Faseb J. Nov2006;20(13):2223-2233). We compared the DRD3 status in the brains of alcohol dependent patients (ADP) to that of healthy controls (CTR) using the DRD3-preferring agonist positron emission tomography (PET) radioligand [11C]PHNO and a selective DRD3 antagonist, to enable the separation of DRD3 and DRD2 contribution to the [11C]PHNO PET signal (Wilson et al. J MedChem. Jun2005;48(12):4153-4160; Graff-Guerrero et al. Int J Neuropsychopharmacol. Sep2009;1-15; Rabiner et al. Synapse. Sep2009;63(9):782-793). Methods: Sixteen male ADP (415±254 days of abstinence) and 13 male CTR matched for age and smoking status were scanned with PET following administration of [11C]PHNO pre- and 3hr-post the administration of a selective DRD3 antagonist (GSK598809 60mg p.o.). Regions examined were: Pallidum, thalamus, ventral striatum, putamen, caudate, hypothalamus, substantia nigra/ventral tegmental area, hypothalamus, and cerebellum. Results&Conclusion: The CTR and ADP groups were well matched for age (41.5±10.3 vs 42.4±9.4 year). The baseline scans for each group were well matched for injected mass of PHNO (20±4 vs 19±3 ng/kg), and injected [11C]PHNO activity (210±58 vs 201±60 MBq). Baseline [11C]PHNO VT was signifi cantly higher in ADP when compared with CTR in hypothalamus (16.5±4 vs 13.7±2.9, p=0.015), a region in which the [11C]PHNO signal in healthy controls almost entirely refl ects DRD3 availability. There were no other signifi cant regional differences in VT between the two groups. No signifi cant relationships between duration of alcohol abstinence and baseline regional VT values in hypothalamus or any other brain region were detected. The reductions in regional VT following a single 60 mg dose of GSK598809 were consistent with those observed in previous studies across all regions (Searle et al. BiolPsychiatry. Aug2010;68(4):392-399). The regional changes in VT following DRD3-blockade were consistent between the two groups, indicating the regional fractions of DRD3 are similar in the two groups. To our knowledge, this is the fi rst study where brain DRD3 levels are assessed in alcohol dependent individuals. This preliminary fi nding of regionally increased DRD3 binding – in hypothalamus but not in striatal regions – adds to the knowledge about the potential role of DRD3 in addiction as well as the role of dopamine in different stages of addiction. Study funding: MRC grant and GlaxoSmithKline.

MG09

SUBJECTIVE RESPONSE TO ALCOHOL IN HARMFUL AND HAZARDOUS DRINKERS: AN ACCEPTABILITY AND FEASIBILITY PILOT STUDY Hasnaoui SK, Faculty of Medicine, Univ of Southampton, Univ Dept of Psychiatry Academic Centre, College Keep 4-12 Terminus Terrace Southampton SO14 3DT [email protected] Carrick OG, Koshnow Z, Brandish E, Garner MJ, Sinclair JMA Dept of Psychiatry, Univ of Southampton

Background: Alcohol Use Disorders (AUDs) represent a substantial health, social and economic burden. Their aetiology is complex but includes an individual’s subjective response (SR) to alcohol, motives for drinking, and expectancies of drinking alcohol. Alcohol outcome expectancies are well established as predictors of drinking behaviour although the majority of previous research has focused on self-report measures of alcohol expectancies. New implicit measures of alcohol expectancies (e.g. expectancy bias) are needed to understand the underlying drinking behavioural processes in alcohol use disorders. Methods: An experimental, double blind, cross-over, within subject study recruited male participants scoring for hazardous/ harmful levels of drinking on the Alcohol Use Disorders Identifi cation Test (AUDIT). They were randomly allocated to receive an alcohol or placebo condition at visit one and the other condition at visit two. The alcohol condition received an alcoholic drink calculated to raise their blood alcohol level (BAL) to 80mg/100ml, based on their BMI and age. Placebo condition received a non-alcoholic drink of equal volume. The Drinking Motives (DMQ-R) and Drinking Expectancies (DEQ-R), and self-reported confi dence in resisting drinking (DRSEQ) Questionnaires were completed at baseline, and the Biphasic Alcohol Effects Scale (BAES) was completed at intervals over 130 minutes post drink. Participants completed a computerised covariation task at 40 minutes, which assessed their initial expectancy and recall bias for alcohol relative to non-alcohol stimuli, and also the perceived contingency between alcohol images and positive, negative and neutral outcomes. In each condition participants were asked to rate the diffi culty of the computerised task (scale 1-5). Results: 20 participants (mean age 23.40) attended both study visits with a mean AUDIT score of 12.5 (SD 3.80). No statistically signifi cant results were observed in post-task covariation estimates between the placebo and alcohol condition. Mean diffi cultly ratings of the covariation task in placebo (2.35) and alcohol conditions (2.70) did not differ signifi cantly. Conclusions: Results suggest participants in the alcohol condition showed no defi cits in task performance demonstrating the covariation task is acceptable and feasible for use in an alcohol challenge test, although further testing using larger samples and different populations is necessary. The research has provided grounding for future work and suggests a new model for implicit testing of alcohol expectancies. Funded by The University of Southampton A44 ABSTRACTS

TA01

GUIDELINES, PRESCRIPTIONS AND TREATMENT RESTRICTIONS IN SECONDARY CARE TREATMENT OF PATIENTS WITH GENERALIZED ANXIETY DISORDER: AN INTERNATIONAL QUESTIONNAIRE SURVEY. Bolognesi F, Univ Dept of Psychiatry, Univ of Southampton Faculty of Medicine, Academic Centre College Keep 4-12 Terminus Terrace Southampton SO14 3DT [email protected] Allgulander C (1), Bandelow B (2), Pallanti S (3), Baldwin DS (4). 1. Karolinska Inst, Stockholm, Sweden; 2. Dept of Psychiatry and Psychotherapy, Univ of Göttingen, Germany; 3. Dept of Psychiatry, Univ of Florence, Italy; 4. Faculty of Medicine, Univ of Southampton

Introduction: Generalized anxiety disorder (GAD) is a common, distressing and impairing condition, often comorbid with other mental disorders and physical illnesses, which imposes a substantial demand on primary and secondary care health services. Little is known about the infl uence of guidelines, formulary restrictions, or the availability of psychological interventions on treatment decisions in routine clinical practice. Methods: An international steering committee developed a multiple choice questionnaire as part of an educational programme. The questionnaire was completed by psychiatrists from 13 countries who attended one of three meetings in 2010. Questionnaires were available in English and other European languages. Results: A total of 411 questionnaires were completed suffi ciently fully to be included in the analysis (‘respondents’, 46%). A reluctance by patients to engage with and continue pharmacological treatment was judged to be uncommon (mean scores 4.2 and 4.9 respectively, where 10 represents ‘always reluctant’). There was a similar perceived lack of reluctance to engage with psychological interventions (mean score 4.2, where 10 represents ‘always reluctant’). National or local guidelines for treatment of GAD infl uenced prescribing decisions in a limited way (mean scores 5.4 and 4.5 respectively, where 10 represents ‘always infl uence’). The majority of respondents indicated they were free to prescribe as they wish (mean score 8.2, where 10 represents ‘totally free’). Despite a common perception that anxiety symptoms in many patients do not respond fully to antidepressant treatment (mean core 5.6, where 10 represents ‘always unresolved’), fi nancial concerns often restricted the ability to prescribe second-line treatments after non-response to fi rst-line antidepressant treatment (mean score 3.8, where 10 represents ‘cost always limits’). Substitution of branded prescriptions with generic alternatives was not uncommon (mean score 4.6, where 10 represents ‘always substituted’). Conclusions: National and local guidelines were reported to have a limited impact on treatment decisions in routine clinical practice. Financial concerns were reported to often infl uence treatment decisions, and generic substitution was considered to be not uncommon, in the secondary care of patients with GAD. Development of the questionnaire and the educational programme was supported by an unrestricted educational grant from Pfi zer Ltd.

TA02

SURVEY ON DISCHARGE LETTERS FOR PATIENTS WITH MIXED ANXIETY AND DEPRESSION, AND ADJUSTMENT DISORDER IN BEDFORD CRISIS RESOLUTION TEAM Dissanayake LK, Psychiatry, South Essex Partnership Trust, Weller Wing, Bedford Hospital, Kempston Road, Bedford MK42 9DJ [email protected] Gadalkarim W (1), Ratnayake TB (2), Sule A(3) (1) Speciality Psychiatrist, Spring House, Biggleswade Hospital, Biggleswade, SG18 0EL (2) Consultant Psychiatrist, Director of Medical Education (SEPT), Weller Wing, Bedford Hospital, Kempston Rd, Bedford, MK42 9DJ (3) Consultant in General Adult Psychiatry at SEPT and Honorary Visiting Research Associate at the Dept of Psychiatry, Cambridge Univ.

Background: Crisis resolution team in Bedford serves approximately 200,000 working age population. Observation indicates a marked proportion suffering with Anxiety disorders. The trust medication policy for management of Anxiety disorders, based on NICE guidelines includes psychological therapy preferably as fi rst line, and pharmacotherapy if indicated. Antidepressants, i.e.: SSRI are indicated in some other anxiety disorders, therefore were not observed in this study. However, pharmacotherapy with antidepressants and antipsychotics are often used even though they are not licensed for conditions such as mixed anxiety and depressive disorder (MADD) and Adjustment disorders. Objective: To investigate a trend of prescription of antidepressants and antipsychotics outside its license for patients with diagnoses of MADD and Adjustment disorder. Method: Data collected randomly and retrospectively from discharge summaries of 2010-2011 included 40 patients. Patients with diagnoses of Adjustment disorder, MADD were included. Exclusion criteria were patients with incomplete discharge summaries, more than one Axis I diagnosis, and other categories of Anxiety disorders such as Generalised Anxiety disorder, Panic Disorder, Phobias and Obsessive Compulsive disorder. The Treatment pattern was analysed including: Patients without medication or on Antidepressants/ Antipsychotics and the reasons were noted. Results: Out of the total of 40, 7 (17.5%) had MADD, 33 (82.5%) had Adjustment disorder. Out of 7 with MADD, 4 (57.1 %) were prescribed antipsychotics and 3 (42.9 %) were prescribed antidepressants. Of the 33 who had Adjustment disorder, 3 (9.1 %) were prescribed antipsychotics, 17 (51.5 %) were prescribed Antidepressants. 13 out of 40 (39.4 %) with either diagnosis weren’t given any medication. In 18/40 (45%) patients the reason for prescription was mentioned. In 10 of this 18 the reason being that it was already started by the GP or other psychiatrists. In 6 (5%), no reason was given for choosing the medication. Conclusion: Though antipsychotics are not licensed for the treatment of MADD and Adjustment disorders, our study indicates a trend towards their use. In reasonable number of discharge summaries, no guidance was given to GP regarding its indications or further review. Therefore it would be benefi cial to take it as a recommendation. The limitations include the fact that acute symptom management with these medications in a crisis was necessary and patients were discharged at shorter intervals, thus limiting the time for review. We also need to consider the validity of the diagnosis made in a crisis situation. There also is a possibility that the plan was discussed with the patient, but not mentioned in the discharge summary. Declaration of Interests: I confi rm that I have completed the Declaration of Interests Form. Keyword: Anxiety Funding: No funding was accepted for the audit.

TA03

SOCIAL ANXIETY IS ASSOCIATED WITH A LOSS OF POSITIVE SELF-REFERENTIAL BIAS IN A PROBABILISTIC SOCIAL LEARNING TASK Button KB, School of Social and Community Medicine, Univ of Bristol, Oakfi eld House, Bristol BS8 2BN [email protected] Lewis G (1) Munafò MR (2) (1) School of Social and Community Medicine, Univ of Bristol, Oakfi eld House, Bristol. BS8 2BN, UK (2) School of Experimental Psychology, Univ of Bristol, Bristol. BS8 1TU, UK

Introduction. Threat biased cognitive processing is thought to cause and maintain social anxiety. Not all patients respond to current cognitive therapies and understanding better the cognitive mechanisms which maintain social anxiety symptoms may help to develop more effective treatments. The ability to use social information to infer what others are thinking, referred to here as social learning, is fundamental for effective social interaction. Social learning may be important in social anxiety which is characterised by fears of negative social evaluation, negative self-evaluations, and a tendency during social situations to adopt an observer perspective (i.e., viewing the self through the eyes of others). This study examined whether social anxiety is associated with biased social learning. Method. One hundred healthy volunteers varying in social anxiety (low n = 33; mid-range n = 32; high n = 35) completed a novel probabilistic social learning task which required participants to learn 3 social rules (i.e., like, neutral, and dislike) across 2 conditions (i.e., self- and other-referential). Results. We found evidence of a positive self-referential learning bias. During the online learning phase individuals responded more positively in the self- relative to the other-referential condition (β = -2.7, 95% CI [-5.3 to -0.1], p = 0.04). This positive bias was strongest for the lowest socially anxious and was abolished with increasing social anxiety in the neutral and dislike rules (social anxiety × referential condition, β = 0.3, 95% CI [0.01 to 0.5], p = 0.04). Conclusions. Low socially anxious individuals automatically discount negative self-referential information giving rise to a positive self-referential learning bias which may be protective for mental health. Social anxiety is associated with a loss of this positive self-referential bias, providing evidence for a putative learning mechanism which may act to confi rm fears of negative evaluation and thus maintain anxiety symptoms. This research was funded by an MRC studentship awarded to KB. ABSTRACTS A45

TA04

DECISION-MAKING IN OBSESSIVE-COMPULSIVE DISORDER: COMPULSIVITY AND HOARDING ARE ASSOCIATED WITH POORER PERFORMANCE Kaser M, Translational Medicine and Therapeutics, Division of Clinical Pharmacology Univ of Cambridge, Addenbrooke’s Hospital, Cambridge, UK, CB2 2QQ, [email protected] Hacioglu M (1), Yildirim EA (1), Saatcioglu O (1) (1) Bakirkoy Research and Training Hospital for Psychiatry, Neurology and Neurosurgery, 34147, Istanbul, Turkey

Introduction: Research on neurobiological substrates of symptom heterogeneity in obsessive-compulsive disorder (OCD) has shown that distinct clusters of symptoms (symptom dimensions) are associated with different neural correlates of fronto-striatal circuits. Decision-making cognition is mediated through a circuit including many critical brain regions implicated in OCD, thus it has been suggested to have a central role in neurocognitive functioning in OCD. However, few studies focused on the effects of symptom heterogeneity on decision-making in OCD. In this study, we aimed to investigate the relationships between decision making cognition and symptom dimensions and clinical features in patients with OCD. Methods: Eighty fi ve patients meeting DSM-IV diagnostic criteria for OCD participated in the study. Decision making cognition was tested with Iowa Gambling Task (IGT); variety of symptoms and symptom dimensions were evaluated with Yale-Brown Obsessive Compulsive Scale(Y-BOCS) - Symptom Checklist and Padua Inventory (PI). Patients were assessed for OCD symptom severity (YBOCS), depression (Hamilton Depression Scale), anxiety (State and Trait Anxiety Inventory). Digit Span, Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST) and Stroop Test were also administered to detect whether IGT performances were affected by other neurocognitive domains. Results: The patients with hoarding compulsions showed signifi cantly worse performance in IGT compared to patients not having hoarding compulsions (p<0.05, Cohen’s d=0.66). Y-BOCS compulsions score was negatively correlated with IGT performance (R2=0.33). According to the factor analysis of PI responses, F4-Harming Concerns factor was positively correlated with IGT performance while the rest of the factors showed no correlation. Multiple regression analyses showed that IGT performance was not affected by other neurocognitive functions, sociodemographic features or depression and anxiety levels. Conclusions: Higher level of compulsivity was associated with poorer decision-making performance in OCD patients. This fi nding might provide further evidence suggesting common neural correlates between impulsivity and compulsivity, as the association between impulsivity and poorer decision-making has also been established. At the other hand, previous reports have shown the association between hoarding compulsions and poorer treatment response to SSRIs and CBT. Negative effect of hoarding compulsions on decision-making might be a neurocognitive manifestation of relatively distinct subgroup of patients associated with poorer decision-making.

TA05

CANNABIDIOL AS A PHARMACOLOGICAL ADJUNCT TO VIRTUAL REALITY EXPOSURE THERAPY IN THE TREATMENT OF ACROPHOBIA Fisher MJ, Clinical Psychopharmacology Unit, UCL, Gower St London England, UK, WC1E 6BT m.fi [email protected] Fisher, MJ(1) Muetzelfeldt, L(1) Swapp, D(2) Curran, HV(1) Morgan, CJA(1) (1) UCL, Clin Psychopharmacol Unit, London WC1E 6BT, England (2) UCL, Dept Comp Sci, London WC1E 6BT, England

Acrophobia, or fear of heights, is a widespread and debilitating anxiety disorder. Virtual reality exposure therapy regimens have been shown to be highly effective for acrophobia treatment. Exposure-based behavioural therapy of anxiety disorders is believed to rely on extinction of fear responses. Cannabidiol (CBD), a non-psychotropic phytocannabinoid, has been shown to possess anxiolytic properties in both animals and humans and preclinical studies have indicated that CBD can also facilitate fear extinction processes. We therefore hypothesized that CBD may be a benefi cial pharmacological adjunct to virtual reality exposure therapy to enhance fear extinction in humans with acrophobia. In a randomized, double-blind placebo-controlled study, 24 subjects with acrophobia were treated with two sessions of exposure therapy using a virtual reality glass elevator in a Computer Automatic Virtual Environment (CAVE tm) to simulate moving up through 10 levels of a skyscraper. 1 hour prior to exposure therapy, CBD or placebo was administered by inhalation using a Volcano® vaporizer. Key outcome measures were scores on the acrophobia questionnaire (AAQ), subjective ratings of anxiety at each of the 10 levels at pre- and post- treatment and at 3 month follow up. Virtual reality exposure therapy was found to signifi cantly reduce fear as measured using the acrophobia questionnaire (AAQ) from pre-treatment assessment to post-treatment assessment and 3 month follow up (p<0.001). CBD signifi cantly enhanced the benefi t of exposure at session 1 compared to placebo on subjective ratings of anxiety during exposure therapy (p=0.038). This study further demonstrates the utility of virtual reality exposure therapy in the treatment of acrophobia. Initial support is provided for the use of CBD as an adjunct to exposure-based psychotherapy to accelerate fear extinction. CBD effects are thought to depend on facilitation of endocannabinoid-mediated neurotransmission by blocking endocannabinoid uptake and/or degradation. Pharmacological potentiation of endocannabinoid signaling during exposure-based therapies may decrease the emotional load during exposures to fear stimuli leading to more effective fear extinction. Funded by grant awarded to Celia JA Morgan by the European College of Neuropsychopharmacology A46 ABSTRACTS

TB01

CAPTODIAMINE, A PUTATIVE ANTIDEPRESSANT, REVERSES ANHEDONIA INDUCED BY CHRONIC MILD STRESS AND EXERTS A SPECIFIC TROPHIC ACTION IN THE HYPOTHALAMUS OF C57/BL6 MICE Ring R, School of Biomolecular and Biomedical Science, Univ College Dublin , Belfi eld, Dublin 4, Ireland [email protected] Regan, CM. School of Biomolecular and Biomedical Science, UCD Conway Inst, Univ College Dublin, Dublin 4, Ireland

We have re-evaluated psychiatric drugs eliminated from the market by the FDA Drug Effi cacy Study (DESI) programme in 1960’s and found one, captodiamine, to be a putative antidepressant. Previously, we demonstrated captodiamine to reverse behavioural despair in C57Bl6 mice and, using receptor over-expression assays in HEK293T cells, demonstrated captodiamine to exert an agonist action at the D3 dopamine receptor and sigma-1 receptor and antagonist activity at the 5-HT2c receptor (Ring et al., 2010 J. Psychopharmacol. 24 [Supp. 3] A50). We have now extended these studies in vivo. All procedures employed C57Bl6 mice chronically treated with captodiamine (5 mg/kg, i.p., 7 days), were approved by the UCD Animal Research Ethics Committee according to EU Council Directive 86–609–EEC, and performed by individuals licensed by the Department of Health. Co-administration of rimcazole (5mg/kg, i.p.), a sigma-1 receptor antagonist, reversed the reduced immobility produced by captodiamine (p = 0.76, Mann Whitney U-test; n = 8]. In contrast, co-administration of ritanserin (4mg/kg, i.p.), a 5-HT2c receptor antagonist, potentiated the action of captodiamine in the forced swim test (p = 0.0043, Kruskal-Wallis test; n = 10). We also demonstrated captodiamine to attenuate the anhedonia induced by chronic unpredictable mild stress using oestrus female urine sniffi ng as a read-out (F [1, 35] = 6.824, p = 0.0132, n=10). We further explored the effect of captodiamine on anhedonia by determining if it exerted a trophic effect on the hypothalamus. Using ELISAs for CRF and BDNF, we found captodiamine to signifi cantly reduce CRF (p =0.0270, Student’s t-test; n = 4) and increase BDNF expression (p =0.0285, Student’s t-test; n = 6), specifi cally in the hypothalamus. As with the forced swim test, BDNF expression was reversed with rimcazole and signifi cantly potentiated with ritanserin (p < 0.05, one-way ANOVA, n = 4). Using an immunoblotting procedure, the captodiamine-induced increase in BDNF resulted in an enhanced expression of hypothalamic synapsin (p = 0.0013, Student’s t-test; n = 4) but was without effect on the PSD-95, a postsynaptic structural protein (p = 0.6262, Student’s t-test; n = 4). Further, rimcazole was found to reverse the captodiamine-induced increase in synapsin expression (p > 0.05, One-way Anova; n = 4). It is concluded that captodiamine may primarily exert its antidepressant action on the hypothalamic-pituitary-adrenal axis. Supported by the Higher Education Authority PRTLI cycle 4 Programme.

TB02

INVESTIGATING THE MECHANISM UNDERLYING DELAYED VERSUS RAPID ANTIDEPRESSANT ACTION USING A NOVEL RODENT MODEL OF AFFECTIVE STATE-INDUCED MEMORY BIAS Stuart SA, School of Physiology and Pharmacology, Univ of Bristol, Medical Sciences, University Walk, Bristol BS8 1TD [email protected] Butler P(1), Nutt DJ(2), Robinson ESJ(3) (1) Global Safety Pharmacology, Pfi zer Worldwide R&D, Sandwich, UK (2) Neuropsychopharmacology Unit, Div of Experimental Medicine, Imperial College, UK (3) School of Physiology and Pharmacology, Univ of Bristol, UK

Currently licensed antidepressant drugs show delayed clinical effi cacy, with subjective improvements in mood observed after several weeks of chronic treatment. The cognitive neuropsychological theory of antidepressant action (Harmer et al.,2003 Am J Psychiatry, 160:990-2) proposes that, whilst these drugs have acute effects on emotional processing biases, their actions are delayed due to the requirement for new, positively biased learning and associated memories. The NMDA receptor antagonist, ketamine has been reported to have a rapid onset of action in depressed patients. We hypothesise that depressed mood arises from pervasive negative memory bias, and predict that ketamine’s rapid action is due to an ability to block this bias during recall. To test if the rate of onset of clinical effi cacy corresponds with the ability of the drug to block memory bias, we compared effects of the delayed onset antidepressant, venlafaxine with ketamine in our novel rodent model of affective state-induced memory bias. The rodent memory bias assay uses a bowl-digging task where rats (male Lister Hooded, n=16) acquire two independent memories for a substrate-reward association using within-subject discrimination learning. Treatment or control was administered prior to substrate-reward pairing sessions, and the absolute reward value was kept consistent across all sessions. 24hrs after the last pairing session, animals were presented with both reward-paired substrates in a choice test and %choice for the treatment-paired substrate was recorded over 30 trials using random reinforcement (1 in 3). Venlafaxine (1.0-10.0mg/kg, i.p. F3,45=4.43, p=0.0082) but not ketamine (1.0-3.0mg/kg, i.p., NS) treatment before learning induced a dose-dependent bias towards the drug-paired substrate at recall. FG-7142 (5mg/kg, i.p.) treatment before learning induced a signifi cant negative memory bias (F3,45=3.72, p=0.018), which was attenuated by ketamine administered prior to recall (p=0.0379). Venlafaxine administered at recall failed to block the FG-7142-induced negative memory bias (NS). These data suggest that venlafaxine positively biases new memories for rewarding experience, but is unable to block the recall of a negative bias associated with previously encoded memories. In contrast ketamine was able to modify the recall of previously learnt, negatively biased memory, an effect which may underlie its rapid onset of action. In this assay, the rate of onset of clinical effi cacy corresponds with actions on memory recall and novel treatments which induce positive memory bias and prevent recall of negative memories could provide a rapid onset antidepressant therapy. SAS supported by BBSRC and Pfi zer, ESJR by RCUK Academic Fellowship and BPS Integrative Pharmacology Fund.

TB03

A POTENTIALLY NOVEL INDEX OF MATERNAL-INFANT BOND: BANDWIDTHS OF B62DF1 MOUSE PUP ULTRASONIC VOCALISATIONS ARE DECREASED BY MATERNAL CHRONIC MILD STRESS, EFFECTS WHICH ARE BLOCKED BY MATERNAL CLOMIPRAMINE TREATMENT Trist AJ, Biomedical Sciences, Univ of Nottingham, Medical School Queen’s Medical Centre Nottingham NG7 2UH, [email protected] Aziz HA (1) Stevenson C (2) Pardon MC (3) (1),(2),(3) Medical School, QMC, Nottingham, NG72UH

Introduction: Postpartum depression (PPD) affects 15% of mothers, with maternal dysphoric symptoms and poor attachment towards the newborn causing developmental cognitive defi cits. The chronic-mild-stress (CMS) model matches construct validity of PPD through gestational stressors, a known risk-factor in humans. Analysis of ultrasonic vocalisations (USVs) during postpartum pup-retrieval tasks may be an indicator of maternal-infant bond, a face validity criterion often overlooked when modelling PPD. We aimed to establish the impact of exposure to gestational CMS and post-partum antidepressant treatment on pup and dam USV emissions during the pup-retrieval task as an indirect index of maternal-infant bond. Methods: 39 B6D2F1 pregnant dams were used. 10 were randomly allocated to the control unstressed group (C, n=10). The other 29 mice were subjected to CMS after the end of the mating period until parturition. The CMS procedure involved the sequential application of mild stressors such as confi nement; paired housing and cage tilt (30°). CMS dams were then randomly allocated into stress-untreated (S, n=9), stress-fl uoxetine (SF, n=10) and stress-clomipramine (SC, n=10) groups. Fluoxetine (20mg/Kg/day) and clomipramine (10mg/Kg/day) were administered via drinking water from parturition. On postpartum day 7, USV recordings were taken from pups alone outside the nest (T1, 2 minutes) and during a pup-retrieval task (T2, 5 minutes) during which latencies to retrieve all pups back to the nest were recorded. Mean number of calls, frequency, bandwidth and duration characteristics were analysed from spectrograms (n=5) for each experimental group and compared using 1-way ANCOVA (litter size as a covariate) followed by post-hoc planned comparisons with (p<0.05) showing signifi cance. Results: T1 pup USV bandwidths differed across groups (p=0.012) with SC and C pups showing larger bandwidths than SF and S: SC>SF (p=0.013), SC>S (p=0.079 ), C>SF (p=0.004) and C>S (p=0.028). T2 pup USVs were unchanged across experimental conditions. Number of dam USVs emitted in T2 differed across groups (p=0.049). SC dams emitted more calls than those in groups C (p=0.040), S (p=0.013) and SF (p=0.029). Conclusions: Prenatal maternal CMS decreased T1 pup USV bandwidths, effects which were attenuated by postpartum maternal clomipramine treatment, implicating bandwidths as a potentially novel indicator of maternal- infant bond. Clomipramine treatment following prenatal CMS increased the number of dam USV emissions in T2 compared to dams in other experimental conditions, implicating the combined role of serotonin and noradrenaline signalling pathways in dam USV production. Thanks to the BAP for providing an In-vivo training award to Adam Trist ABSTRACTS A47

TB04

CHRONIC AND ACUTE PHYSICAL ILLNESS IN THE CHILD: EFFECT OF EXPOSURE TO MATERNAL STRESS DURING PREGNANCY Wertz JW, Inst of Psychiatry, King’s College London, Centre for the Cellular Basis of Behaviour, The James Black Centre 125 Coldharbour Lane, London SE5 9NU [email protected] Kanani R (1), Flynn S (1), Plant D (1), Pariante CM (1), Pawlby S (1) (1) Centre for the Cellular Basis of Behaviour The James Black Centre 125 Coldharbour Lane London SE5 9NU ntroduction: Stress during pregnancy has repeatedly been shown to be associated with negative outcomes in the children of affected mothers, particularly in relation to behavioural, cognitive and emotional measures. In contrast, the impact of stress during pregnancy on the offspring¹s physical health has been less well researched. The aim of the present study was to extend previous research by examining indicators of acute and chronic physical health in a prospective cohort of children whose mothers were assessed for experience of stressful life events during pregnancy. Methods: Stressful life events were assessed in a random community sample of 151pregnant women recruited from two general practices in South London. Information on acute and chronic physical illness in the offspring was obtained through interviews with the mothers when the child was 4 years old. Results: Children of mothers who experienced more than one stressful life event during pregnancy had a signifi cantly higher risk of suffering from a chronic medical condition (p < 0.05). This effect was particularly strong for life events associated with pregnancy (p < 0.01) but was not present when acute physical health was examined as an outcome variable. Stressful life events experienced after pregnancy or related to birth did not have any effect on children¹s physical health. The effects of stressful life events on physical health remained signifi cant after birth weight, maternal smoking and drinking during pregnancy were taken into account; however, they were reduced to non-signifi cance when antenatal depression was included in the analysis. Conclusions: This study shows that experience of stressful live events during pregnancy is related to a higher incidence of chronic medical conditions in the offspring of affected mothers, mediated through the occurrence of antenatal depression. The fi nding that experience of stressors after pregnancy did not have such an effect suggests that stressful live events and depression experienced during pregnancy induce biological changes in the foetus that render the unborn child susceptible for the development of chronic illness later in life, underscoring the importance of efforts of targeted interventions to reduce their impact on pregnant woman. Funding for this study was provided by Medical Resaerch Council, The Mental Health Foundation and the South West GP Trust.

TB05

EXPOSURE TO DEPRESSION IN UTERO PREDICTS CHILDHOOD MEDICAL PROBLEMS Plant DT, Psychological Medicine, Inst of Psychiatry, King’s College London, 2-059 James Black Centre 125 Coldharbour Lane London SE5 9NU dominic.plant@ kcl.ac.uk Pariante CM(1), Pawlby S(1) (1) Inst of Psychiatry, KCL, London SE5 9NU

Introduction: Exposure to depression in utero is associated with emotional and behavioural diffi culties in middle childhood. Less is known about the impact of maternal antenatal depression on offspring childhood physical health outcomes. We tested the hypothesis that exposure to antenatal depression increases the risk of childhood medical problems. Furthermore, we investigated the relationship between childhood psychopathology and physical ill health. Methods: The sample included 178 families from the South London Child Development Study. A prospective longitudinal design was employed. Mothers provided data on their current mental state and physical health during pregnancy through clinical interview. Maternal reports of offspring childhood physical ill health were provided through clinical interview at 4 and 11 years postpartum. Teachers reported on offspring emotional and behavioural diffi culties at 11 years using the Strengths and Diffi culties Questionnaire. Results: The risk for major or chronic illness during the fi rst 11 years of life was signifi cantly greater among offspring exposed to depression in utero (OR = 6.18), compared to offspring not so exposed. This effect was independent of other maternal characteristics such as mothers’ prior physical health problems, mothers’ physical illness during pregnancy and mothers’ smoking during pregnancy. Furthermore, offspring who suffered physical ill health between birth and 11 years exhibited greater emotional and behavioural problems at age 11. Conclusions: Detection of depression during pregnancy can identify offspring who are at an increased risk of physical health problems in later childhood. This study was supported by the MRC UK, the Psychiatry Research Trust and the South West GP Trust.

TB06

WORKING MEMORY PERFORMANCE IN POSTPARTUM PSYCHOSIS Pauls AM, Neuroimaging and Psychosis Studies, Inst of Psychiatry, Centre for Neuroimaging Sciences (PO89), King’s College London Denmark Hill London SE5 8AF [email protected] Mehta MA(2), O’Daly OG(2), Pawlby S(3), Ciufolini S(1), Hazelgrove K(1), Veccio C(1) Williams SCR(2), Pariante CM(3), Dazzan P(1) (1)Dept of Psychosis Studies, Inst of Psychiatry, King’s College London, De Crespigny Park, SE5 8AF (2)Dept of Neuroimaging, Inst of Psychiatry, King’s College London, De Crespigny Park, SE5 8AF (3)Dept of Psychological Medicine, Inst of Psychiatry, King’s College London, De Crespigny Park, SE5 8AF

Postpartum psychosis (PP) is the most severe postpartum psychiatric illness occurring within weeks after delivery (Kumar et al., 1995, Journal of Affective Disorders, 33, 11-22). Working memory (WM) impairments are associated with bipolar disorder (Jogia et al., 2011, World Journal of Biological Psychiatry, 0, 1-11) and psychosis unrelated to childbirth (Fusar-Poli et al., 2011, Journal of Psychiatric Research, 45, 190-198) and represent an unmet treatment need. It is not known whether women at risk of PP have similar impairments in WM performance or associated brain networks. We compared WM performance across women at risk of PP, with PP, and healthy controls using an fMRI N-back paradigm. Thirty-three women were scanned on average 15 weeks postpartum (range 4-43 weeks) including 13 at risk of PP due to a diagnosis of bipolar (N=10), or schizoaffective disorder (N=2), or a family history (N=1) (Spinelli, 2009, American Journal of Psychiatry, 166, 405-408); eight with a personal history of PP; and 12 healthy controls. Data were acquired on a 3 Tesla (TR/TE=2000/30ms) and pre-processed and analysed in SPM8. Statistical signifi cance was defi ned as p<.05 corrected for multiple comparisons on the basis of cluster extent across the whole brain. Participants were required to respond to a series of letter stimuli when they matched a target (control) or the stimulus presented 1-, 2- or 3-back. There were no signifi cant group differences in age (Mean=33.4 years, standard deviation=5.05), IQ (104, 8.98), or weeks after delivery (15.82, 10.64). The PP group scored signifi cantly higher than healthy controls (at-risk group being intermediate) in the general pathology scale (F2, 30=6.141, p<.01) and the negative symptom scale of the Positive and Negative Symptom Scale (F2, 30=3.45, p<.05). There were not signifi cant differences between groups in brain activation. However, when we compared the speed-accuracy trade-off between groups we found a signifi cant difference, with the at-risk group having a faster reaction time but making more errors compared to both, the control and PP group (F1, 30=3.71, p<.0.05). Women in the at-risk group showed a higher speed-accuracy trade-off compared to both, the control and PP group, suggesting a different response strategy in this group. This impairment may be related to the history of bipolar disorder in this group, or suggest an effect of chronicity of their psychiatric disorder. Our results differ from those found in other psychoses unrelated to childbirth, suggesting that women with PP do not carry a WM impairment as psychosis-vulnerability indicator. The research was funded by the Psychiatry Research Trust (PRT) and the National Alliance for Research on Schizophrenia and Depression (NARSAD). A48 ABSTRACTS

TB07

WHEN LESS IS MORE: INVESTIGATING WORKING MEMORY IN PATIENTS RECOVERED FROM DEPRESSION Norbury R, Univ Dept of Psychiatry, Univ of Oxford, Warneford Hospital Oxford , Oxford [email protected] Godlewska B(1) Cowen PJ(1) (1) Univ Dept of Psychiatry,Warneford Hospital,Oxford

Major depressive disorder (MDD) is associated with abnormalities in working memory and it is possible that the problems with planning and concentration often reported in depression arise from defi cits in this cognitive domain. To date, neuroimaging studies of working memory in MDD have almost entirely focused on the acute phase. Collectively these studies suggest that, while maintaining similar performance to healthy controls, MDD patients show greater activation in frontal regions and reduced deactivation in limbic cortex. It is less clear, however, if this dysfunctional pattern of activation persists when depressive symptoms improve. The current study, therefore, employed Functional Magnetic Resonance Imaging (FMRI), in combination with a simple verbal n-back task, in a cohort of recovered MDD patients (rMDD). The following specifi c hypotheses were tested: 1) Recovered MDD would show increased dorsolateral prefrontal activation as function of task complexity; and 2) Recovered MDD would show reduced deactivation of limbic cortex as function of increasing task complexity. Thirty right-handed participants were recruited (healthy controls (HC) n = 15). During FMRI scanning participants completed a verbal n-back task with three levels of complexity (1-,2- and 3-back) and a sensorimotor control task (0-back). Functional MRI data were acquired on a 3T Siemens Tim Trio System and processed using standard approaches. Signifi cant activations across the whole brain were identifi ed using cluster-based thresholding of statistical images with a height threshold of Z > 2.3 and a (whole-brain corrected) spatial extent threshold of P = .05. In a priori regions of interest (ROIs) appropriate small volume corrections were applied. There were no between-group differences in n-back performance. For quadratic load responsivity rMDD was associated with increased BOLD response in bilateral hippocampus (left: Z = 3.35, P = .002, right: Z =2.97, P = .02) . For overall capacity (n-back vs. 0 -back) both groups showed signifi cant activations in frontal, parietal and cingulate cortex. However, contrary to our original hypothesis, there were no signifi cant between-group differences in terms of overall capacity. In sum, our data suggest that rMDD is associated with reduced deactivation in limbic cortex during a working memory task, a phenomenon similar to that reported in acute MDD and young people at increased risk of familial depression. It should be noted, however, that we did not observe the hyperfrontality previously reported in MDD in this sample of rMDD. It is possible, therefore, that increased frontal activation refl ects a state marker of acute depression, whereas limbic noise (also reported in MDD) may refl ect a trait vulnerability marker for MDD. Funding for this work was provided by the Medical Research Council.

TB08

MMRM OR LOCF FOR ASSESSING EFFICACY IN MDD: RESULTS FROM A RANDOMISED PLACEBO- AND COMPARATOR-CONTROLLED STUDY Baldwin DS, Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, Univ of Southampton, UK, Univ Dept of Psychiatry Academic Centre, College Keep 4-12 Terminus Terrace, Southampton SO14 3DT [email protected]

Introduction: The traditional approach to analysing data from randomised clinical trials in major depressive disorder (MDD) has been ‘last observation carried forward’ (LOCF), due to its simplicity and conservatism. The mixed model for repeated measurements (MMRM) methodology has been discussed as a more valid choice of statistical methodology for the primary analysis. The relative merits of LOCF and MMRM in analysing effi cacy outcomes are considered in relation to data from a recent multi-centre randomised placebo- and comparator-controlled trial of a novel psychotropic drug (Lu AA21004) [Baldwin DS et al., 2012 European Neuropsychopharmacology doi:10.1016/j.euroneuro.2011.11.008]. Methods: The study was of the effi cacy, safety, and tolerability of Lu AA21004 versus placebo, using duloxetine as active reference, in patients with MDD. Patients were randomly assigned to 2.5, 5 or 10mg Lu AA21004, placebo, or 60mg duloxetine. The 5mg and 10mg doses of Lu AA21004 were tested separately versus placebo at p≤0.025 in a pre-specifi ed order. The primary effi cacy analysis was an analysis of covariance (ANCOVA) of the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 8 (full analysis set [FAS], LOCF), with treatment and site as factors and baseline MADRS as a covariate. Sensitivity analyses were performed based on observed cases (OC) data, using both ANCOVA and MMRM. All continuous endpoints were analysed similarly. Results: In the primary effi cacy analysis (mean change from baseline in MADRS total score at Week 8, FAS, ANCOVA, LOCF), differences to placebo (n=145) of -1.7 (Lu AA21004 5mg, n=155) and -1.5 points (Lu AA21004 10mg, n=151) were not statistically signifi cant; nor were those for Lu AA21004 2.5mg (-1.4 points, n=155) or duloxetine (-2.0 points, n=149). However, MMRM analyses of the primary endpoint [-2.5 points (p=0.018) for Lu AA21004 5mg, -2.6 points (p =0.014) for Lu AA21004 10mg, and -3.0 points (p=0.006) for duloxetine] and most secondary endpoints (HAMD, HAMA, CGI-I) were supportive of likely effi cacy for Lu AA21004 5mg and 10mg and for duloxetine. Conclusions: Although this study is considered ‘failed’, based on LOCF analysis of the primary outcome measure for both Lu AA21004 and the comparator (duloxetine), use of the MMRM approach would have resulted in a different outcome, confi rming the effi cacy for duloxetine and supporting effi cacy for Lu AA21004 5mg and 10mg. These fi ndings highlight the need for sensitivity analyses and contribute to discussions regarding the most appropriate method for analysing data in randomised controlled trials, specifi cally in studies that provide data intended for drug registration. Funding: The randomised controlled trial was sponsored by H. Lundbeck A/S and the Takeda Pharmaceutical Company, Ltd. On behalf of his employer, DSB received consulting fees for planning and supervising the study, and personal support for travel to study-related meetings.

TB09

TREATMENT AND OUTCOMES FOR PATIENTS WITH DEPRESSION WHO ARE PARTIAL RESPONDERS TO SSRI TREATMENT: POST-HOC ANALYSIS FINDINGS FROM A EUROPEAN OBSERVATIONAL STUDY Lenox-Smith A, Eli Lilly and Company, Lilly House, Priestley Road Basingstoke Hampshire RG24 9NL [email protected] Quail D(1), Martinez J(2), Classi P(2) (1) Eli Lilly and Company, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH; (2) Eli Lilly and Company, Indianapolis, IN 46285, USA

Introduction: The FINDER study was a European observational study designed to investigate the impact of depression and its treatment on health-related quality of life. To help better understand the epidemiology of partial response to SSRI treatment in real-world settings, we report descriptive data on the response to SSRI treatment in FINDER at 3 months, and the subsequent treatment choice and 6-month outcome in partial responders. Methods: This was a descriptive post hoc analysis. Hospital Anxiety and Depression Scale depression subscale (HADS-D) scores were calculated at baseline, 3 and 6 months. Depressed patients (i.e., ‘cases’, defi ned as patients with HADS-D score >10 at baseline) who only had taken SSRI(s) for 3 months were categorized at the 3-month visit as follows: Remitter, HADS-D score ≤7; partial responder, HADS-D score >7 and ≥25% improvement from baseline in HADS-D; non-responder, HADS-D score >7 and <25% improvement from baseline in HADS-D. For partial responders at 3 months, treatments in the 3-6 month study period and outcomes at 6 months were determined. Results: Overall, 1147 patients with depression had taken SSRI(s) during the fi rst 3 months. At 3 months, 451 (39.3%) were in remission, 317 (27.6%) were partial responders and 337 (29.4%) were non-responders (3.7% had missing data). Of those 317 patients who were partial responders to SSRI(s) at 3 months, 260 (82.0%) continued on SSRI drugs only for the next 3 months, 16 (5.0%) received no treatment, 3 received SNRI drugs only, 3 received combination treatment, 2 received TCA drugs only, and 1 received other drugs only (32 patients had missing data). At 6 months, 41 (12.9%) of the 3-month partial responders were non responders, 99 (31.2%) remained partial responders and 151 (47.6%) were remitters (26 had missing data). Conclusions: In these analyses from FINDER, 27.6% of patients who met caseness criteria for depression at baseline and received treatment with SSRI(s) were considered partial responders at 3 months. At 6 months, 47.6% of the 3-month partial responders achieved remission. Given the importance of remission as the goal of treatment for patients with major depression, these data underscore an unmet need for patients with partial response to SSRI treatment. Financial Disclosure: This study was funded by Eli Lilly and Company ABSTRACTS A49

TB10

EARLY INCREASE IN A NEURONAL INTEGRITY MARKER WITH ANTIDEPRESSANT TREATMENT OF MAJOR DEPRESSION: 1H-MAGNETIC RESONANCE SPECTROSCOPY OF N-ACETYL-ASPARTATE Taylor MJ, Dept of Psychosis Studies, Inst of Psychiatry, London SE5 8AF [email protected] Godlewska BR(1), Norbury R(1,2), Selvaraj S(1,3), Near J(1), Cowen PJ(1) (1) Univ Dept of Psychiatry, Warneford Hospital, Oxford OX3 7JX (2) Oxford Centre for Clinical Magnetic Resonance Research (OCMR), John Radcliffe Hospital, Oxford OX3 9DU (3) Dept of Psychosis Studies, Inst of Psychiatry, King’s College London, London SE5 8AF

Increasing interest surrounds potential neuroprotective or neurotrophic actions of antidepressants. While growing evidence points to important early clinical and neuropsychological effects of antidepressants, the time course of any effect on neuronal integrity is unclear. N-acetyl-aspartate (NAA) is a marker of neuronal integrity, synthesised within neuronal mitochondria that can readily be measured using the safe, non-invasive technique of magnetic resonance spectroscopy. This study used magnetic resonance spectroscopy to assess effects of short-term treatment with escitalopram on NAA. 39 participants with major depression were randomly assigned to receive either escitalopram 10mg or placebo daily in a double-blind, parallel group design. On the seventh day of treatment, PRESS data were obtained from a 30x30x20 mm voxel placed in medial frontal cortex. Age and gender-matched healthy controls who received no treatment were also scanned. Levels of NAA were signifi cantly higher in patients treated with escitalopram (1.13 ± .19) than in either placebo-treated patients (.99 ± .16, p<.01) or healthy controls (.96 ± .18, p<.01). Our fi ndings are consistent with proposition that antidepressant treatment in depressed patients can produce early changes in neuronal integrity. Future studies should clarify whether an early change in NAA could be a possible early biomarker of treatment effect in depressed patients. Financial sponsorship: This study was funded by the Medical Research Council. Dr Taylor was a National Institute for Health Research Clinical Lecturer through the Oxford University Clinical Academic Graduate School (OUCAGS).

TB11

THE ROLE OF POLYUNSATURATED FATTY ACIDS ON INTERFERON-ALPHA INDUCED CLINICAL FACTORS Hepgul N, Psychological Medicine, Inst of Psychiatry, King’s College London 2.3A CCBB, James Black Centre, 125 Coldharbour Lane, London SE5 9NU [email protected] Baraldi S(1), Bufalino C(1), Gray(2), Sanders T(2), Hotopf M(1), Henderson M(1), Cleare AJ(1), Agarwal K(3), Pariante CM(1) (1) Dept of Psychological Medicine, Inst of Psychiatry, King’s College London (2) School of Medicine, Kings’ College London (3) King’s College Hospital

Interferon-alpha (IFN-α) is the standard treatment for chronic hepatitis C virus (HCV) infection. This treatment clears the virus, but induces major depression and other neuropsychiatric adverse effects in 30-50% of subjects, which in turn can affect quality of life and treatment response. This high rate of depression is consistent with the evidence that increased infl ammatory processes participate to the pathogenesis of major depression. However, the exact biological mechanisms underlying this depression are still not clear. Polyunsaturated fatty acids (PUFAs) have been shown to play an important role in both infl ammation and depression. The aim of this study is to investigate changes in PUFA levels and clinical factors such as: depression, fatigue and stress, during IFN-α treatment. We recruited 23 patients with chronic HCV infection (mean±SEM age: 45.0±10.6 years). Subjects were assessed using a prospective cohort design, at baseline (immediately before treatment begins) and at treatment week 12 (TW12) of IFN-α therapy. Severity of psychopathological symptoms was assessed using the Inventory of Depressive Symptomatology (IDS). Fatigue levels were assessed using the Chalder Fatigue Questionnaire and levels of stress using the Perceived Stress Scale (PSS). Plasma levels of three PUFAs; docosahexaenoic acid (DHA), eicosapapentaenoic acid (EPA) and arachidonic acid (AA), were measured in a sub-sample of 13 patients (age: 43.2±11.0 years) at the same time points. Levels of PUFAs are presented as percentage of total fatty acids. Data were analysed using SPSS. Paired samples t-tests were used to compare changes in scores between baseline and treatment week 12. Depression, fatigue and stress scores were all signifi cantly higher at TW12 when compared to baseline (mean±SEM: 23.0±3.1 vs. 12.9±2.6, p=0.002, 22.0±1.6 vs. 16.5±1.4, p=0.001 and 16.4±1.7 vs. 13.3±1.5, p=0.026 respectively). The PUFAs DHA and EPA were both lower at TW12 when compared to baseline (1.6±0.1 vs. 1.8±0.2, p=0.07 and 0.4±0.0 vs. 0.6±0.1, p=0.05, respectively). AA levels were signifi cantly higher at TW12 when compared to baseline (6.0±0.5 vs. 5.3±0.4, p=0.03). Furthermore, baseline DHA levels were signifi cantly correlated with stress and fatigue scores at TW12 (Spearman’s rho=-0.5 p=0.034 and r=-0.6 p=0.021, respectively). PUFAs may play an important role in IFN-α-induced depression, fatigue and stress, due to their anti-infl ammatory and neuroprotective properties. This suggests we might be able to identify and target more vulnerable individuals among patients due to commence IFN-α therapy, to prevent poorer outcomes. Future studies would need to clarify if the changes in PUFA levels are also related to changes in infl ammatory markers. This research was funded by a joint National Institute for Health Research (NIHR), Biomedical Research Council (BRC) strategic project award.

TB12

FURTHER EVIDENCE ON THE ANTIDEPRESSANT EFFICACY OF 3ß-METHOXY-PREGNENOLONE (MAP4343) IN EXPERIMENTAL MODELS: EFFECTS IN TREE SHREWS (TUPAIA BELANGERI) EXPOSED TO CHRONIC PSYCHOSOCIAL STRESS Parésys L, Psychopharmacology, MAPREG, 78 rue du Général Leclerc Le Kremlin Bicêtre France, 94270 [email protected] Hoffmann K(2), Bate S(3), Baulieu EE(1), Fuchs E(2), Bianchi M(1) (1) MAPREG Psychopharmacology, Le Kremlin-Bicêtre, France (2) Clinical Neurobiology Lab, German Primate Center, Gottingen, Germany (3) Huntingdon Life Sciences, Huntingdon, England

MAP4343 (3beta-methoxy-pregnenolone) has antidepressant effi cacy in rats isolated from weaning (Bianchi and Baulieu, 2012, PNAS 109:1713-8). MAP4343 specifi cally binds the microtubule associated protein-2 (MAP2) and modulates brain microtubule function. The antidepressant effi cacy of MAP4343 is here investigated in the chronic psychosocial stress model in tree shrews. Tree shrews are small day-active mammals, closely related to primates and with important translational relevance for stress research (Fuchs, 2005, CNS Spectr. 10: 182-189). Bodyweight, urinary cortisol, noradrenaline and testosterone levels were investigated. The expression of markers of microtubule dynamics, MAP2 and synaptic markers was also detected in the prefrontal cortex (PFC). Adult male tree shrews (n=16) were submitted to eight weeks of an established experimental protocol consisting of two fi rst weeks of undisturbed conditions (control weeks) followed by six weeks of psychosocial stress. During the two fi rst weeks of stress (stress weeks) the animals received daily per os administration of the vehicle while during the four following weeks (treatments weeks) received daily per os administration of either MAP4343 (50mg/kg, n=8) or the vehicle (n=8). Urine was collected daily and cortisol, noradrenaline and testosterone were quantifi ed. PFC was dissected 24h after the last drug / vehicle administration and processed for Western blot of microtubule dynamics markers, phosphoMAP2/MAP2, pre-synaptic (synaptophysin) and post-synaptic (PSD-95) markers. Total alpha-tubulin was used as housekeeper. Hormones, bodyweight and molecular data were analysed using a repeated measures mixed model analysis approach, followed by pre-planned comparisons to compare treatments. Results are expressed as mean±SEM. Bodyweight and testosterone were decreased by stress and MAP4343 was ineffective in counteracting these stress-induced responses. However, MAP4343 blocked the stress-induced increase in noradrenaline compared to vehicle (p<0.01) and had a similar tendency on the stress-induced cortisol increase, but the latter was not signifi cant. In the PFC, MAP4343 has no effects on microtubule dynamics markers. PhosphoMAP2/MAP2 was increased by MAP4343 in the right PFC (1.08±0.05, p<0.01) and decreased in the left PFC (0.97±0.09, p<0.05) compared to vehicle. This was accompanied by decreased synaptophysin (0.95±0.07, p<0.05) and increased PSD95 (1.09±0.09) in the right PFC compared to vehicle, while increased synaptophysin (1.09±0.07, p<0.01) was detected in the left PFC. Our results show that MAP4343 appears to block the increase in hormonal levels related to stress response. These effects were accompanied by differential changes in phosphoMAP2/MAP2 and synaptic proteins in the right and left PFC suggestive of modulation of microtubule function and synaptic remodelling. Supported by the Eurostars project DEPSTER. A50 ABSTRACTS

TB13

EFFECTS OF SSRIS ON BODYWEIGHT, HORMONES AND HIPPOCAMPAL MICROTUBULAR AND SYNAPTIC PROTEINS IN FEMALE TREE SHREWS (TUPAIA BELANGERI): COMPARISON WITH MAP4343 (3ß-METHOXY-PREGNENOLONE) Leandri J, Psychopharmacology, MAPREG, 80 rue du Général Leclerc Le Kremlin Bicêtre France 94276 [email protected] Hoffmann K (1), Bate ST (2), Baulieu EE (3), Fuchs E (1), Bianchi M (3). (1) Clinical Neurobiology Lab, German Primate Center, Gottingen, Germany; (2) Huntingdon Life Sciences, Huntingdon, England; (3) MAPREG, Le Kremlin-Bicêtre, France.

Tree shrews are small mammals related to primates of translational relevance for psychopharmacology research (Fuchs, 2005, CNS Spectr. 10:182-189). Here the effects of selective serotonin reuptake inhibitors (SSRIs) like escitalopram and fl uoxetine are compared with those of MAP4343 (3β-methoxy-pregnenolone) on bodyweight, hormones and hippocampal microtubular and synaptic proteins in naïve female tree shrews. MAP4343 specifi cally binds the microtubule associated protein 2 (MAP-2) and has rapid antidepressant effi cacy in experimental models (Bianchi and Baulieu, 2012, PNAS 109:1713-1718). Adult female tree shrews were left undisturbed one week (basal levels) and then daily administered per os for 21 days with either fl uoxetine (15 mg/kg, n=6), escitalopram (15 mg/kg, n=6), MAP4343 (50mg/kg, n=8) or the vehicle (n=6). Urine was collected daily for measurement of cortisol and estrone. Twenty-four hours after the last administration, hippocampi were dissected and processed for Western blot of microtubule dynamics markers (Tyr/Glu-Tub, Acet-Tub and Δ2-Tub), pre-synaptic (synaptophysin) and post-synaptic (PSD-95) markers. Total α-tubulin was used as housekeeper. Hormones, bodyweight and molecular data were analysed using a repeated measures mixed model analysis approach, followed by pre-planned comparisons to compare treatments. Results are expressed as mean±SEM. Escitalopram and MAP4343 did not affect bodyweight, while fl uoxetine decreased bodyweight to 9±0.7% of basal level by day 21 of treatment (p<0.05). Cortisol increased as a stress response to the per os administrations in all groups, except escitalopram which decreased the response at day 21 of treatment (p<0.01). Estrone was not affected by any treatment. Escitalopram decreased Tyr/Glu-Tub, Acet-Tub and Δ2-Tub in the right and left hippocampus compared to vehicle (p<0.001). Tyr/Glu-Tub:Acet-Tub ratio suggests that escitalopram increased microtubule dynamics in the left hippocampus (1.42±0.14) compared to vehicle (p<0.01). This was accompanied by decreased synaptophysin in the right (0.79±0.09, p<0.05) and left (0.60±0.03, p<0.01) hippocampus compared to vehicle. Fluoxetine decreased Δ2-Tub (0.93±0.03, p<0.05) and synaptophysin (1.09±0.05, p<0.01) in the right hippocampus compared to vehicle. In contrast, MAP4343 increased (p<0.01) synaptophysin (1.69±0.14) in the left hippocampus, while microtubular proteins were not affected. PSD-95 was not changed by any treatment. SSRIs induced long-lasting changes on hippocampal microtubular proteins accompanied by decreased synaptophysin. The bodyweight decrease induced by fl uoxetine and the high magnitude of effects of escitalopram on microtubular proteins may raise questions about SSRIs tolerability in female animals. In contrast, MAP4343 did not alter bodyweight or hormonal levels and showed no long-lasting changes of microtubular proteins, despite a persistent effi cacy in increasing synaptophysin. Supported by the Eurostars project DEPSTER.

TB14

ACTIVATION OF SEROTONIN RECEPTORS IN HUMAN HIPPOCAMPAL PROGENITOR CELLS AFFECTS GENE EXPRESSION OF THE GLUCOCORTICOID RECEPTOR AND NERVE GROWTH FACTOR INDUCIBLE FACTOR A Musaelyan K, Psychological Medicine, Inst of Psychiatry, King’s College London, Room 2-054, The James Black Centre 125 Coldharbour Lane London SE5 9NU [email protected] Anacker C (1), Zunszain PA (1), Pariante CM (1) (1) The James Black Centre, Room 2-059 125 Coldharbour Lane London SE5 9NU

Recent studies investigating antidepressants’ mechanism of action highlighted the involvement of the glucocorticoid receptor (GR) in the hippocampus as being strongly implicated in the hypothalamo-pituitary-adrenal axis regulation (Pariante et al., Br J Pharmacol 139: 1111–1118, 2003). Few studies however addressed the interaction between GR and serotonergic signalling, the main target of the most currently used antidepressants. In vivo and in vitro rat studies suggested that activation of serotonin receptors causes an increase in the hippocampal GR activation and binding via a nerve growth factor inducible factor A (NGFI-A) dependent mechanism (Mitchell et al., Neuroscience 48: 631-639, 1992; Weaver et al., J. Neurosci. 27, 1756-1768, 2007). In this study we investigated whether this mechanism is present in the human hippocampal progenitor cells. The human hippocampal progenitor cell line HPC03A/07 from ReNeuron, UK, was used in this study as a unique in vitro model of human hippocampal neurogenesis. To investigate the effect of activation of serotonergic receptors on GR function, cells were treated with 5-carboxamidotryptamine (5-CT), a serotonin receptor agonist with the highest affi nity for 5-HT1A and 5-HT7 receptors. After 24 and 72 hours of the treatment, RNA was extracted and gene expression was assessed by quantitative real-time PCR. The results demonstrate that treatment with 5-CT decreases the GR and NGFI-A gene expression. More specifi cally, 24 hour exposure to 5-CT (at 1μM) resulted in 23.16% decrease in NGFI-A gene expression (N=4, p<0.05). At this time-point, a trend towards a decrease in the GR expression could already be observed (13%, p>0.05). The 72 hour treatment decreased GR expression by 19% (N=4, p<0.001) while NGFI-A expression remained decreased by 13% (N=4, p<0.05). In conclusion, we demonstrate that in human hippocampal progenitor cells, activation of serotonergic receptors causes an initial decrease in NGFI-A expression, followed by a decrease in GR gene expression. Our previous work has demonstrated decreased GR expression as a result of GR activation by SSRI antidepressants in the same hippocampal progenitor cell model (Anacker et al., Mol Psychiatry 16, 738-50, 2011). As our data demonstrates that NGFI-A downregulation precedes GR downregulation, we suggest that serotonin receptor activation may activate the GR and subsequently decrease GR gene expression via an NGFI-A-mediated mechanism. This research is supported by the South London and Maudsley NHS Foundation Trust & Institute of Psychiatry NIHR Biomedical Research Centre for Mental Health and the Commission of European Communities 7th Framework Programme Collaborative Project Grant Agreement n°22963 (Mood Infl ame). ABSTRACTS A51

TB15

MR- AND GR-DEPENDENT MOLECULAR PATHWAYS DIFFERENTIALLY REGULATING HUMAN HIPPOCAMPAL NEUROGENESIS Anacker C, Psychological Medicine, Inst of Psychiatry, King’s College London, Centre for the Cellular Basis of Behaviour, The James Black Centre Room 2-059 125 Coldharbour Lane London SE59NU [email protected] Cattaneo A (2), Musaelyan K (1), Zunszain PA (1), Thuret S (1), Price J (1), Pariante CM (1) (1) Inst of Psychiatry, King’s College London, UK (2) Genetics Unit, IRCCS, Giovanni di Dio, Brescia, Italy

Depressed patients and chronically stressed animals display reduced adult hippocampal neurogenesis, possibly contributing to the development of depressive symptoms upon exposure to stress. Chronic stress increases glucocorticoid hormones, and moreover, administration of glucocorticoids to rodents impairs hippocampal neurogenesis and precipitates depressive-like behaviour. Here we wanted to investigate the unknown molecular mechanisms by which glucocorticoids regulate hippocampal neurogenesis in humans. Specifi cally, we wanted to investigate the effects cortisol on its high affi nity mineralocorticoid receptor (MR) and its low affi nity glucocorticoid receptor (GR), and identify subsequent changes in molecular signalling pathways and neurogenesis in human hippocampal progenitor cells. We treated human fetal hippocampal progenitor cells (HPC03A/07, ReNeuron,UK), with cortisol (1nM-100μM), the MR-antagonist, spironolactone (1μM) and the GR-antagonist, RU486 (50nM). Proliferation, neurogenesis and astrogliogenesis were assessed using immunocytochemistry for incorporated 5’-bromo-3’-desoxyuridine (BrdU,10μM), for microtubulin-associated protein 2 (MAP2)-positive neurons and S100 calcium binding protein (S100ß)-positive astrocytes. Gene expression microarray and pathway analysis were performed using GeneAtlas platform (Affymetrix) and Pathway Studio software (Ariadne). We found that low concentrations of cortisol (1nM-100nM) increase cell proliferation (1nM by ~4%,p>0.05; 10nM by ~9%,p>0.05; 100nM by 15%,p=0.001; n=5) whereas high concentrations (1μM-100μM) decrease proliferation (1μM by ~2%,p>0.05; 10μM by ~5%,p>0.05; 100μM by ~14%,p=0.001; n=5). The MR-antagonist, spironolactone, blocked the increase in cell proliferation upon treatment with low cortisol concentrations, while the GR-antagonist, RU486, blocked the decrease in proliferation upon high concentrations. Cortisol at low (100nM) and high concentrations (100μM) decreased neuronal differentiation into MAP2-positive neurons by ~24% (p=0.005, n=3) and by ~22% (p=0.002; n=3), respectively. Again, the decrease in neurogenesis for the low concentration was blocked by spironolactone while the decrease upon high concentrations was blocked by RU486. Low concentrations of cortisol (100nM) increased differentiation into S100ß-positive astrocytes by ~23% (p=0.003, n=3), an effect again blocked by spironolactone. The high concentrations of cortisol did not regulate the number of astrocytes. Molecular pathway analysis identifi ed that cortisol inhibits Hedgehog-signalling independent of the concentration (at 100nM p=0.0002; at 100μM p=0.0048), while only MR activation by low cortisol concentrations activated Notch-signalling (p=0.00003), and only GR activation by high cortisol concentrations inhibited the TGFß/SMAD-pathway (p=0.0011). In conclusion, our data demonstrate for the fi rst time that cortisol exerts differential, dose-dependent effects on human hippocampal neurogenesis and astrogliogenesis, which are mediated by MR-dependent regulation of Hedgehog- and Notch-signalling, and by GR-dependent regulation of Hedgehog- and TGFß/SMAD-signalling. This project was funded by the Commission of European Communities 7th Framework Programme Collaborative Project Grant n22963 (MoodInfl ame).

TB16

ANTI-INFLAMMATORY ACTION OF ANTIDEPRESSANTS IN HUMAN HIPPOCAMPAL STEM CELLS Horowitz MA, Centre for the Cellular Basis of Behaviour, Dept of Psychological Medicine, Inst of Psychiatry, King’s College London, 125 Coldharbour Lane, London SE5 9NU [email protected] Zunszain P(1), Anacker C(1), Musaelyan K(1), Pariante C(1) (1) SPI-lab, Inst of Psychiatry, King’s College London

Infl ammation has been implicated as an important process in the pathogenesis of depression (Raison and Miller, 2011). The ability of antidepressants to suppress infl ammation has been demonstrated in a variety of animal cell lines and human peripheral blood samples, although there have been confl icting results (Janssen et al., 2010; Xie et al. 1996). Here we investigate the anti-infl ammatory effect of antidepressants from different chemical classes in human hippocampal stem cells. Infl ammation was induced by incubation with interleukin (IL)-1b for 24 hours and infl ammatory response was quantifi ed by measurement of IL-6 secreted into the supernatant by means of ELISA. Expression of both auto-induced IL-1 and IL-6 was measured by real time PCR after 12 and 24 hours of incubation. Three antidepressants from different chemical classes – moclobemide (a reversible monoamine oxidase inhibitor), agomelatine (a melatonergic agonist) and venlafaxine (a serotonin-noradrenaline reuptake inhibitor) were co-incubated with IL-1b for 24 hours for protein determination of IL-6 and for 12 and 24 hours for gene expression measurement of IL-1 and IL-6. Each antidepressant demonstrated a dose-dependent suppression of the infl ammatory response to IL-1b upon co-incubation as measured by IL-6 protein expression. Venlafaxine reduced IL-6 detected by 26% (p<0.01) at 1uM and 22% (p<0.05) at 10uM; agomelatine reduced IL-6 by 31% (p<0.05) at 1uM and 29% (p<0.05) at 10uM. Moclobemide showed a trend towards decreasing IL-6 by 20% and 26% at doses of 1uM and 10uM respectively. Preliminary data suggests that gene expression of IL-1 and IL-6 does not change with antidepressant co-incubation at 12 or 24 hours, suggesting a non-transcriptional means of regulating infl ammation by antidepressants . Overall, our results add to the body of evidence suggesting that antidepressants have anti-infl ammatory actions, irrespective of their differential affi nities for monoaminergic receptor subtypes. Funding: NARSAD Yound Investigator award to P.Z.; Studentship from King’s College London Graduate School to M.H.; A52 ABSTRACTS

TB17

INFLAME-BEAT: UNDERSTANDING THE ROLE OF INFLAMMATION IN PREDICTING DEPRESSION IN PATIENTS WITH HEART DISEASE Nikkheslat N, Dept of Psychological Medicine, Inst of Psychiatry, Kings College London, The James Black Centre 125 Coldharbour Lane London SE5 9NU naghmeh. [email protected] Nikkheslat N(1,3), Tylee A(4), Pariante CM(1), Carvalho LA(1,2) (1) Inst of Psychiatry, King’s College London, The James Black Centre, 125 Coldharbour Lane, London SE5 9NU (2) Univ College London,1-19 Torrington Place, London WC1E 7HB (3) Univ of Roehampton, Holybourne Avenue, London SW15 4JD (4)Health Service and Population Research Dept, Inst of Psychiatry, King’s College London, London, UK.

Introduction: The prevalence of depression among patients with established coronary heart disease (CHD) in considerably higher as compared to the general population. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients greatly increasing the risk of cardiovascular morbidity and mortality (Miller et al., 2002, The American Journal of Cardiology, 90: 1279-1283). However, the physiological mechanisms underlying the increased incidence of depression in patients with CHD are yet to be understood. Alteration of the hypothalamic-pituitary-adrenal axis is observed in a signifi cant proportion of patients with major depression and seems to refl ect an impaired ability of glucocorticoid hormones to exert their physiological effects (glucocorticoid resistance) (Pariante, 2006, J Psychopharmacol, 20: 79-84). The aim of this work was to investigate the possible mechanisms involved in development of depression in patients with heart disease. Methods: The Infl ame-Beat project is a 2-year prospective cohort study. The primary goal is to test the hypothesis that activated infl ammatory response in patients with CHD is associated with future development of depressive symptoms. CHD patients with depression (n=31) and without (n=74) were recruited and assessed for depressive symptoms by means of Beck depression inventory (BECK). Plasma cortisol measurement was carried out using a commercially available ELISA kit (R&D®). Peripheral blood mononuclear cells (PBMC) were separated and stored for measurement of glucocorticoid receptor (GR) sensitivity. The protocol for culturing frozen PBMC has been optimised and GR sensitivity is currently being investigated. Gene expression of GR total, its subtype GR1F, and NFKB- a transcription factor involved in the cellular responses to stress, and inhibited by glucocorticoids – were conducted via RT-PCR. Results: Cortisol was signifi cantly lower in depressed patients (CHD-d), compared to non-depressed patients (CHD-d 293.58 + 18.458, CHD 354.72 + 17.560, p=0.019). Glucocorticoid receptor total expression (CHD-d 1.08 + 0.07, CHD 1.16 + 0.13, p=0.217), its subtype GR1F expression (CHD-d 1.22 + 0.11, CHD 1.08 + 0.12, p=0.364), or NFKB – (CHD-d 1.06+ 0.07, CHD 1.09 + 0.09, p=0.815) did not differ between depressed and non-depressed CHD patients. Conclusions: Depressed patients with CHD had lower levels of cortisol than non depressed CHD patients. Decreased levels of cortisol were not due to glucocorticoid receptor numbers. We hypothesize that decreased cortisol levels will be due to increased glucocorticoid sensitivity in depressed CHD patients. This project is funded by the NARSAD and ECNP Young Investigator Award to Livia Carvalho, and the European Union Framework 7.

TB18

A 5-HT2A RECEPTOR POLYMORPHISM IS ASSOCIATED WITH THE DEVELOPMENT OF SEROTONIN SYNDROME FOLLOWING ANTIDEPRESSANT TREATMENT Yevtushenko OO, Dept of Neuropharmacology, Inst of Pharmacology and Toxicology AMS Ukraine, Eugene Potie str., 14, Kyiv, Ukraine , 03057, o.yevtushenko@qub. ac.uk Oros MM (1), Reynolds GP (2) (1) Clinic “Vodolij”, Pachovs’kogo str., 14 , Khust, 90400 Ukraine (2) Biomedical Research Centre, Sheffi eld Hallam Univ, UK.

Serotonin syndrome (SS) is potentially life-threatening condition which develops as a result of increasing serotonin activity in the central nervous system. This condition can develop following therapeutic use of some medications, including antidepressant drugs. The cause of SS is poorly understood and is most likely multifactorial; pharmacogenetic factors are likely to account for the substantial variability between individuals in the emergence of this syndrome. In this study, the functional promoter polymorphisms –1019 G/C of the 5-HT1A and -1438A/G of the 5-HT2A receptor genes as well as ins/del polymorphism of the 5-HT transporter were investigated for their association with the development of SS following antidepressant treatment of 180 subjects with panic disorder. Drug treatment was with sertraline (n=74), paroxetine (n=28), escitalopram (n=43), mirtazapine (n=35) as monotherapy in standard therapeutic doses. Genomic DNA was extracted from blood samples and genotypes determined using standard PCR protocols. SS was diagnosed according to Hunter serotonin toxicity criteria (Dunkley et al. 2003 QJM 96: 635–42), which included spontaneous or inducable clonus, tremor, hyperrefl exia, hypertonia and hyperthermia. Probability of association was determined by the chi2 or Fisher exact tests. 11 (6%) patients developed SS which manifested with muscle hypertonus, tremor and hyperrefl exia. Change in bowels habits, vomiting, agitation and confusion were also present. There was no signifi cant association of SS with individual drug type (p=0.65). The -1438A/G 5-HT2A receptor polymorphism was signifi cantly associated with the presence of SS. Thus, in GG genotype SS was present in 9/50 patients, and in AA/AG carries presence of SS was 2/130, p<0.001. There was no signifi cant association of SS with the 5-HT1A receptor –1019 G/C polymorphism: 3/42 in GG genotype and 8/138 in C allele carriers, p=0.75. A trend to association of 5HTT ins/ del polymorphism with SS failed to reach signifi cance: 1/64 in ins/ins genotype and 10/116 in del allele carriers, p=0.058. A combination of 5-HT2A and HTT genotypes indicated that carriage of the GG genotype and a del allele was associated with a 25% (8/32) probability of developing SS; the probablility was 2% (3/149) in the absence of these two risk factors (p<0.0001). The results show that -1438A/G 5-HT2A receptor polymorphism is strongly associated with the development of SS in patients treated with antidepressant drugs. A larger study may indicate whether there might be an additive effect or perhaps epistatic interaction of the HTT ins/del polymorphism. These fi ndings indicate the opportunity for genetic testing of risk for a severe and potentially fatal side effect of antidepressant drug treatment. This study recieved no specifi c funding support.

TB19

COGNITIVE DYSFUNCTION AND MOOD DISORDER: A SYSTEMATIC REVIEW Rock PL, Psychiatry, Univ of Oxford, Warneford Hospital, Oxford OX3 7JX [email protected] Roiser, JP(1), Riedel, WJ(2), Blackwell AD(3) (1) Inst of Cognitive Neuroscience, 17 Queen Square, London, WC1N 3AR (2) Dept of Neuropsychology & Psychopharmacology, 6200 MD Maastricht (3) Dept of Psychiatry, Addenbrooke’s Hospital, Cambridge, CB2 0QQ

Cognitive impairment is frequently observed in patients suffering from mood disorder. For example, around two-thirds of patients with depression experience cognitive defi cits that in turn predict poor response to antidepressant treatment. However, it remains unclear whether cognitive dysfunction is a core feature of mood disorders or if it is secondary to symptoms of low or elevated mood. We completed a systematic review of studies employing the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess cognitive function in depression and bipolar disorder (PubMed and PsycINFO; 9 February 2012). Weighted effect sizes refl ecting the performance of patients relative to controls were calculated for each of 11 tests that assessed aspects of cognition including attention, visual memory, executive function and working memory. Relative to controls, symptomatic patients with unipolar depression showed impairments in attention (effect size (Cohen’s d )=0.89), visual memory (effect sizes ranging from 0.44 to 0.54), spatial working memory (effect size=0.52) and executive function (effect sizes ranging from 0.35 to 0.55). Defi cits were found to persist in each of these domains during remission (effect sizes ranging from 0.38 to 0.64). Patients with bipolar disorder demonstrated defi cits during episodes of mania (effect sizes ranging from 0.54 to 1.44) and to a lesser extent during depression (effect sizes ranging from 0.1 to 0.49). Cognitive impairment was also seen in bipolar patients during periods of euthymia (effect sizes ranging from 0.36 to 0.97). Cognitive dysfunction is a key feature of mood disorder that appears to persist following recovery from episodes of depression or mania and is at least in part separable from these mood symptoms. Therefore, impairments in memory, attention and executive function may represent valuable targets for future pharmacological treatments. This research was supported by Cambridge Cognition. ABSTRACTS A53

TB20

THE RELATIONSHIP BETWEEN ASTHMA AND BIPOLAR DISORDER. A NATIONWIDE PHARMACOEPIDEMIOLOGICAL STUDY Svendal G, Dept of Psychiatry, Inst of Clinical Medicine, The Univ of Bergen, Sandviken Hospital, Pb. 23 Sandviken, 5812 Bergen, Norway gjertrudsvendal@hotmail. com Fasmer OB (1), Engeland A (2), Williams L (3), Berk M (3), Lund A (1) (1) The Univ of Bergen, Sandviken Hospital, Pb. 23 Sandviken, 5812 Bergen, Norway (2) The Univ of Bergen, Dept of Public Health and Primary Health Care, Postboks 7804, 5020 Bergen, Norway (3) The Univ of Melbourne, Dept of Clinical and Biomedical Sciences, Barwon Health, PO Box 281, Geelong, VIC 3220.

INTRODUCTION: Studies have revealed there may be an association between psychiatric disorders and asthma (Wamboldt MZ et al., 1996, J Am Acad Child Adolesc Psychiatry, 35, 1042-1049.; Goodwin RD et al., 2003 Arch Gen Psychiatry, 60, 1125-1130). For example, anxiety disorders and ADHD seem to be more prevalent among children and adolescents with asthma (Fasmer OB et al., 2011, J Atten Disord,15, 564-571.; Sansone RA et al., 2008 Psychiatry, 2008, 5, 48-52.). However, few studies have investigated whether persons with asthma have a higher prevalence of bipolar disorder. METHODS: To investigate the comorbidity between asthma and bipolar disorder, the Norwegian Prescription Database for 2006 is utilised. This database encompasses the total Norwegian population of 4.6 million people. Odds ratios were calculated using binary logistic regression. Medications included in the analyses were mood stabilizers in treatment for bipolar disorder, and anti asthmatic drugs. The medications were used as proxies for the disorders. Medication used in treatment for asthma may also be used in treatment for COPD. Because of this we chose to exclude those older than 49 years of age, who are more likely to be diagnosed of COPD. RESULTS: In 2006 there were 3.115.517 persons younger than 49 years of age in Norway. Of this population 176.387 persons (5,7%) received treatment for asthma, while 10.817 (0,35%) received treatment for bipolar disorder. Persons receiving anti asthma drugs had a 2.3-fold increased odds (OR 2.3, 95% CI 2.2, 2.4) of receiving medication for bipolar disorder compared to the non-asthmatic population. When comparing women and men, we found that women (OR 2.5, 95%CI 2.3,2.7) had an increased likelihood of receiving medication for both bipolar disorder and asthma than men (OR 1.9, 95%CI 1.7, 2.1). CONCLUSION: This study revealed a strong positive association between the prescription of medication in treatment for asthma and mood stabilizers in treatment for bipolar disorder. This association was stronger for women than men. Sources of fi nancial sponsorship: This study was founded by the University of Bergen, Norway and MoodNet research group, Haukeland university hospital, Bergen, Norway.

TB21

ATTITUDES OF EUROPEAN PSYCHIATRISTS REGARDING USE OF LONG-ACTING INJECTIONS IN BIPOLAR DISORDER Patel MX, Dept of Psychosis Studies, Inst of Psychiatry, KCL, 16 DeCrespigny Park Box 68 London SE5 8AF [email protected] Scott J (1), Tacchi M-J (1) (1) Univ of Newcastle, Newcastle, UK

Introduction: There is increasing evidence that oral second generation antipsychotics (oral SGAs) are more effective than mood stabilisers for maintenance treatment for bipolar disorder. Consequently, there may be an associated increasing role for antipsychotic long-acting injections (LAIs), particularly in terms of manic relapse prevention and where oral medication adherence is problematic. LAIs have long been used in relapse prevention for schizophrenia and clinicians’ attitudes to LAIs may underpin the wide variation seen in utilisation rates. We aimed to investigate clinicians’ attitudes and knowledge regarding LAI use for bipolar disorder as these cannot be assumed to be the same as those for schizophrenia. Method: This was a cross-sectional questionnaire quantitative pilot study for a convenience sample drawn from Europe which comprised 30 specialists for patients with bipolar disorder. A pre-existing questionnaire was adapted for purpose (Patel MX et al, 2010, Journal of Psychopharmacology, 24, 1473-1482). Data collection was conducted in 2010. Results: The mean number of patients with bipolar disorder per participant was 96 and the mean number on a LAI per participant was 10. Fifty-seven percent of participants reported that their use of LAIs for bipolar disorder over the past 5 years had increased. If participants themselves had bipolar disorder, 43% would not agree to personally take an antipsychotic LAI as a mood stabiliser. 64% believed that the most common reason for prescribing an LAI in bipolar disorder was a history of poor adherence with an oral mood stabiliser. Regarding patient choice, 70% of participants believed that patients always prefer to have oral mood stabiliser instead of an LAI, and 52% believed that patients always prefer to have oral antipsychotic medication instead of an LAI. Over half believed that side effects are worse for LAIs than oral SGAs (55%). Attitudes were moderately strongly positively correlated with knowledge (r= 0.66, p< 0.001). Conclusions: This study is the fi rst to explore attitudes and knowledge underpinning LAI use for bipolar disorder. In general there are similarities in attitudes, both positive and well-informed and negative and less knowledgeable, about the use of LAIs in bipolar disorder and schizophrenia. This suggests that general education and information strategies may be utilised for clinicians who specialise in working with either disorder. Nonetheless, LAI use is likely to remain a third line mood stabiliser option for bipolar disorder, after lithium or anticonvulsants and then oral SGAs. This study was funded by an investigator initiated grant from Janssen-Cilag. A54 ABSTRACTS

TC01

RHYTHMIC DAY/NIGHT VARIATION IN HISTONE ACETYLATION IN THE HIPPOCAMPUS OF C57BL/6 MICE Oyegbami O, School of Psychology/School of Pharmacy, Univ of Nottingham, East Drive, University Park NG7 2RD [email protected] Oyegbami O(1,2,) Collins HM(2), Pardon MC(3), Heery DM(2) & Moran PM(1) 1School of Psychology, 2School of Pharmacy, 3School of Biomedical Sciences, Univ of Nottingham, Nottingham NG7 2RD UK

Introduction: Reversible histone acetylation is a key feature of regulated gene expression that shows disruption in many pathologies, including memory dysfunction. Acetylation of histones H2B and H4 in the hippocampus is associated with memory consolidation in rodents (Bousiges et al 2010, Neuropsychopharmacology 35, 2521– 2537), but is reduced in conditions of memory dysfunction/cognitive decline such as ageing and models of Alzheimer’s Disease (Graff et al., 2012, Nature, In Press). Previous studies in mice have demonstrated that histone acetylation may be subject to circadian control, as bulk histone acetylation levels showed rhythmic (night>day) variation in peripheral organs such as heart (Curtis et al 2004, Journal of Biological Chemistry 279(8): 7091-7097) and liver (Etchegaray et al 2003, Nature 421(6919): 177-182).). We therefore investigated whether rhythmic histone acetylation is observed in C57/BL6 mouse brain and peripheral tissues. Moreover, we assessed bulk histone acetylation in the brain in the APP/PS1 transgenic mouse model of Alzheimer’s disease (APPswePS1dE9), which develop histopathological and behavioural changes at approximately six months of age. Methods: In the fi rst experiment, 14-15 week old male and female wild-type C57BL/6J mice were used. Home cage activity of the mice was measured across the 24 hour circadian cycle and recorded over four days. Mice were sacrifi ced at the two time points which corresponded to the highest and lowest activity; ZT2 and ZT14. In the second experiment 24hr home cage activity was measured over four days in male 18-22 week old APP/PS1 mice and their littermate WT controls. Mice were sacrifi ced at ZT4. Histone acetylation (H2A, H2B, H3 and H4) was measured using western blots in the hippocampus, cerebellum, cortex and striatum. Results: The data confi rmed increased behavioural activity at night (P<0.05). A signifi cant increase in both H2B and H4 acetylation was observed in the hippocampus at night compared to morning in C57BL/6J mice (P<0.05). There was a signifi cant increase in H2B acetylation in the cerebellum of APP/PS1 mice compared to WT controls (P<0.05). Conclusions: Our data provide preliminary evidence for rhythmic (day/night) variation in bulk acetylation of selected histones in mouse hippocampus. If confi rmed, this may provide insight into the fl uctuation of memory symptoms across the circadian cycle in conditions such as Alzheimer’s disease. The APP/PS1 mouse model of Alzheimer’s disease was associated with abnormal H2B acetylation in the cerebellum suggesting that acetylation abnormalities may occur prior to the age at which behavioural abnormality and histopathology is detected. Self-funded

TC02

LOCOMOTOR ACTIVITY MEASURED OVER A 24H PERIOD USING TELEMETRY IS SUBSTANTIALLY HIGHER IN NK1R-/- MICE ONLY DURING THE DARK PHASE Dudley JA, University College London, London WC1E 6BT [email protected] Moyes AJ(2), Stanford SC(1), Hunt SP(1) (1) University College London, London WC1E 6BT (2) Queen Mary Univ London, London EC1M 6BQ

The Neurokinin-1 receptor knock-out (NK1R-/-) mouse expresses defi cits in cognitive performance that resemble those in Attention Defi cit Hyperactivity Disorder (ADHD). In the Light/Dark Exploration Box (LDEB) NK1R -/- mice also exhibit hyperactivity, which is prevented by d-amphetamine (d-AMP) or methylphenidate (Yan et al. 2010, J Psychopharmacol., 24, 27-38). These psychostimulants are fi rst-line treatments for ADHD. However, the LDEB enables measurement of activity for only short periods of time, is moderately stressful, and testing is done in the light phase when mice are least active. We therefore sought an alternative method for screening hyperactivity in these mice. Telemetry allows animals to remain in their home cage where their activity can be recorded continuously over several days. After testing homozygously bred wildtype (WT) and NK1R-/- mice, we investigated whether the hyperactivity was also evident in littermate pairs derived from heterozygous matings. 6 male pairs of WT and NK1R-/- mice (129/SvxC57BL/6 crossed with an outbred MF1 strain) were implanted subcutaneously with a telemetry transmitter (TA-F10, Data Science International). 3 pairs were from homozygous parents and 3 pairs were littermates. Seven days later, the home cages were placed on telemetry mats and animals’ activity was recorded for 2 min every 15 min over 48 h. The light phase was from 8.00 to 20.00 h. Data from the second 24 h of recording were analysed using Friedman’s χ2. NK1R-/- mice from homozygous and heterozygous parents were more active than WT mice in the dark phase (χ2=24.147, P<0.001 and χ2=7.517, P<0.01, respectively). NK1R-/- mice from the homozygous colony were also more active in the light phase (χ2=15.513, P<0.001), although the mean activity was low (WT: 1.26; NK1R-/-: 2.85). This effect was not seen in the littermate pairs. A lack of functional NK1R induces hyperactivity in the dark phase regardless of breeding method. Like WT mice, NK1R -/- mice are nocturnally active, indicating normal circadian rhythms. An increase in activity in the light phase was only apparent in the homozygously bred mice. These fi ndings suggest that there is an effect of early environment on hyperactivity and that telemetry could be developed as a screen for drugs that are effective in patients with ADHD. Supported by the MRC and BBSRC.

TC03

THE ACUTE EFFECTS OF A 5HTP SUPPLEMENT ON DAYTIME MOOD, PERFORMANCE AND SUBJECTIVE NIGHT SLEEP Alford CA, Psychology Dept, Univ of the West of England, Coldharbour Lane, Bristol BS16 1QY [email protected] Davies S (1) (1) Psychology Dept, Univ of the West of England, Coldharbour Lane, Bristol BS16 1QY

Introduction – food supplements are widely sold though there are few controlled studies to assess their potential benefi ts and advertising claims. 5HTP is a serotonin precursor claimed to improve both sleep and mood though clinical evidence is still preliminary (Ioveno N et al 2011 J Affect Dis 130, 343-357), and an experimental study revealed impairment on the Iowa gambling task (Gendle M and Golding A 2010 Hum Psychopharm 25, 491-499). This study examined the acute effects of 5HTP in volunteers. Methods – three male and thirteen female healthy young adults (18-23 years) underwent pre-treatment baseline, placebo comparator - vitamin C 500mg [including zinc] and 5HTP 100mg [including Vitamin C, Niacin, Vitamin B6, Zinc, Folic Acid and Biotin] (Healthspan(R)) taken twice daily (5HTP 200mg/ day) administered using a repeated measures, double-blind, balanced order design. Laboratory assessments comprised subjective mood (Bond and Lader VAS scales), performance (Penscreen.com: Arrows-Go Stop, rapid visual information processing, Sternberg memory scanning) assessed in the afternoon at baseline and on the second day of dosing. Subjective night sleep at home (Leeds sleep evaluation questionnaire – LSEQ) was assessed after the fi rst day of dosing. Results - Data were analysed using ANOVA (baseline, Treatment A, Treatment B) for mood and performance, as well as paired t tests for LSEQ assessing signifi cant (P<0.05) differences. Subjective sleep revealed only trends (P=0.1) for improved sleep onset and more diffi culty waking with 5HTP compared to placebo comparator. In contrast, assessments on the second treatment day revealed improved Go Stop reaction times (P<0.01) and n correct (P<0.03) with 5HTP compared to baseline, but with the placebo comparator (vitamin C) against baseline for memory scanning (p<0.03). 5HTP compared to the comparator improved Go Stop performance (n correct, P<0.02) but impaired memory scanning (n correct, P<0.04). Subjective mood was improved from baseline after 5HTP and the comparator refl ecting likely placebo effects. However, participants also felt more friendly (P<0.05) and calm (P<0.03) after 5HTP compared to comparator. Conclusions – The trends for improved sleep onset but increased diffi culty waking after 5HTP are consistent with a sedative hypnotic effect. In contrast, effects on performance were mixed indicating both improvements compared to baseline, although against the vitamin C comparator improvement with just one measure (Go Stop n correct), yet impairment for memory (n correct). These results contrast with each other, and the improvement with the earlier fi nding of impairment on the gambling task. However, 5HTP did produce a subjective anxiolytic effect against the comparator. No fi nancial sponsorship was received for this study ABSTRACTS A55

TC04

SEVERITY OF INSOMNIA, ATTENTIONAL CONTROL AND THOUGHT INTRUSIONS IN HEALTHY VOLUNTEERS Baker LD, Psychology, Univ of Southampton, Shakleton Building 44 Southampton SO17 1BJ [email protected] Lymn, J (1), Wingfi eld, M (1), Winmill, L (1) Wickens, R. (2) Baldwin, DS.(1), Garner, M. (1) (1) Univ of Southampton (2) Univ of Cardiff

Background: Using subjective self-report questionnaires and experimental measures of executive attention and response inhibition, we previously demonstrated that poor sleep in healthy individuals is associated with increased negative affect and poorer cognitive control (Baker et al., J Psychopharmacol 2010; 24 [suppl.3]: A26). In this new cohort we examine whether specifi c components of poor sleep are associated with attentional defi cits observed in anxiety; a lesser ability to focus attention in accordance with a task instruction, and an increase in failure to inhibit negative thoughts. Method: 110 undergraduates completed a self-report measure of insomnia severity (Insomnia Severity Index, ISI) with three components: severity, impact and distress. Measures of trait anxiety (Spielberger State-Trait Anxiety Index, STAI-T), attentional control (Attentional Control Scale, ACS) and cognitive failures (Cognitive Failures Questionnaire, CFQ) were also completed. Participants completed a 3-stage worry task: an initial 5-minute breathing interval; a 5-minute worry period: and a 5-minute post-worry breathing interval. Thoughts were sampled 12 times during breathing intervals. Results: Higher scores on the ISI were associated with higher levels of anxiety (STAI-T) (r=.46**). Higher scores on both scales were associated with increased cognitive failures (ISI: r=.28**, STAI: r=.60**) and decreased attentional control (ISI: r=-.24*, STAI: r=-.51**). In the pre-worry period, higher ISI total scores, particularly on the severity component, were associated with decreased ability to focus attention upon breathing (total: r=-.24*, severity: r=-.31**). Higher ISI total scores, particularly on the severity and impact sub-scales, were associated with increased negative thought intrusions (total: r= .25**, severity: r= .25**, impact: r= .20*), with severity holding predictive value over and above associations with anxiety (r= .20*). In the post-worry period ISI scores remained predictive of ability to focus attention upon breathing (total: r=-.19, p=.05). No signifi cant associations were found between ISI scores and negative thought intrusions, though trends were observed for impact and satisfaction components (p values: .06, .08). Trait anxiety was modestly related to attentional focus and negative thought intrusions (r=-.21*, r=.36**). No correlations were found between anxiety/insomnia and neutral and positive thought intrusions. Conclusions: In healthy volunteers increased insomnia severity, independent of anxiety, was associated with increased defi cits in attentional control and increased negative thought intrusions during a fi ve-minute breathing focus. Findings align with suggestions that acute episodes of poor sleep may dysregulate key emotion processing networks (e.g. amygdala-prefrontal cortex) implicated in attentional control, and accord with research into sleep deprivation, suggesting preferential processing of negative information following disruption to this circuitry.

TC05

NEUROPSYCHOLOGICAL AND HPA-AXIS CORRELATES OF SLEEP IN HEALTHY SUBJECTS: IMPLICATIONS FOR BIPOLAR AFFECTIVE DISORDER Moriarty AS, Academic Psychiatry, Inst of Neuroscience, Campus for Ageing and Vitality, Newcastle Univ ,Newcastle upon Tyne NE4 5PL [email protected] Bradley AJ(1), Anderson KN(2), Watson S(1), Gallagher P(1), McAllister-Williams RH(1) (1) Academic Psychiatry, Inst of Neuroscience, Newcastle Univ NE4 5PL (2) RVI Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, NE1 4LP

Numerous studies have reported evidence of neuropsychological impairment in Bipolar Disorder (BD), thought to constitute an endophenotypic disease trait (Robinson & Ferrier 2006. Bipolar Disorders 8:103-116). This impairment forms a major source of morbidity in patients and is inadequately treated given the poor current understanding concerning the aetiology. A signifi cant focus of current research is the role of HPA-axis dysregulation. However an additional potential contributor is sleep disturbance which affects 70% of BD patients. Circadian instability has been explored as a disease trait of BD (Ko & Takahashi 2006. Hum. Mol. Genet.15:271–277). Patients also have higher anxiety around sleep and misperceive their own sleep quality (Harvey et al. 2005. Am. J. Psychiatry.162:50-57). In healthy subjects, sleep is known to affect cognition, particularly attention, although, as in BD, the relationship with HPA-axis function is poorly defi ned. The aim of this preliminary study was to investigate, in healthy subjects, the association between sleep, HPA-axis function and the cognitive functions commonly impaired in BD. Subjective sleep parameters were measured using validated sleep questionnaires (Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index) in 21 healthy male subjects. Overnight oximetry excluded sleep apnoea. Subjects were tested using a battery of neuropsychological tasks, including the Attention Network Test (measures performance of alerting, orienting and executive networks) and the Newcastle 2D Spatial Working Memory (SWM) Task. HPA-axis parameters (afternoon cortisol at 4pm, 5pm and 6pm) were measured. Bivariate correlation analysis was used to investigate associations between outcome measures. Two signifi cant relationships were observed. Firstly, a negative correlation between daytime sleepiness and performance of the orienting attentional network (Spearman’s rho=0.43,p=0.030). Furthermore, daytime sleepiness was associated with increased mean afternoon cortisol (Spearman=0.51,p=0.026) which in turn was associated with decreased orienting effect (Spearman=-0.61,p=0.005). Secondly, a correlation (Spearman=0.53, p=0.013) was found between decreased subjective sleep quality and an increased error rate in SWM tasks. These fi ndings suggest that daytime sleepiness may be associated with decreased performance of the orienting network, possibly mediated by an increase in afternoon cortisol. From these data we can hypothesise that sleep-related attentional defi cits may contribute to cognitive impairment in BD. In addition, SWM impairment in BD patients may be related to patient’s underestimation of their own sleep quality. This suggests that simple psychotherapeutic and behavioural techniques focussing on sleep hygiene may have a role in the management of cognitive impairment in BD. Further studies are planned in a cohort of BD patients to further explore these fi ndings. Funded by a grant from the Jenifer Cole Charitable Trust. A56 ABSTRACTS

TD01

BEHAVIOURAL EVALUATION OF A RAT MODEL OF ASD FOLLOWING GESTATIONAL EXPOSURE TO VALPROATE Damany MD, School of Biomedical Sciences, Univ of Nottingham, Medical School, Queen’s Medical Centre Nottingham NG7 2UH [email protected] Shelley S (1); Hirst J (1); Roope E(1); Hodgkinson C (1); Mediratta N (1), Fone K (1), Ebling F (1), Wigmore P (1) (1) School of Biomedical Sciences Univ of Nottingham Medical School Queen’s Medical Centre Nottingham, NG7 2UH

Background: Autistic Spectrum Disorders (ASD) is a heterogeneous pervasive developmental disorder characterised by a core triad of behavioural symptoms; reduced social interaction, impaired communication and repetitive behaviour. Prenatal exposure to valproic acid (VPA), a widely prescribed anticonvulsant, increases the risk of developing ASD and induces teratogenic neurodevelopmental aberrations in rat offspring resembling symptoms seen in humans. The absence of effective treatment and poor understanding of the neurobiological cause of ASD warrant development of a reliable animal model for the disorder. This study characterised the behavioural profi le of rat offspring from Lister-Hooded rat dams given valproate during gestation to further validate this animal model in a rat strain not previously used for this paradigm. Methods: Pregnant Lister-Hooded rat dams received VPA (600mg/kg s.c.) or saline (1ml/kg s.c.) control on gestational day 12.5. 22 VPA and 21 control (male and female) pups were sequentially examined, from postnatal day 36, in locomotor activity, novel object recognition, elevated plus maze (EPM), social interaction (SI), prepulse inhibition of acoustic startle (PPI) and conditioned emotional freezing response (CER) paradigms to evaluate behavioural changes akin to those seen in ASD. Results: Valproate rats of both genders showed greater weight gain (ANOVA main effect treatment p<0.001) than controls. Only male offspring from valproate treated dams were unable to distinguish the novel from a familiar object in NOR (gender x treatment P<0.05). In the SI paradigm there was a main effect of valproate irrespective of gender only on the frequency spent following (p=0.0137) but not in any other behaviour components. In contrast, there were no valproate mediated changes in either PPI or CER. In the EPM, only male VPA rats exhibited more stretch-attend postures (p=0.05) than male controls, suggesting increased anxiety, yet no similar changes were seen in females. Other behaviours showed gender dependent variation but this was unaffected by valproate. Conclusions: This model bore striking resemblance to some aspects of human autism. Prenatal VPA exposure in rats caused gender specifi c visual learning and memory impairment, limited defi cits in SI and increased anxiety; all having translational relevance to common ASD features. Unlike other strains, VPA in Lister hooded rats increased weight gain but failed to alter PPI and locomotor activity. Further studies are required to characterise the face validity of the model and evaluate the ability of potential novel therapies to reverse or prevent development of the symptoms.

TD02

IS ALTERED LEARNING AND MEMORY IN A PRENATAL VALPROATE ANIMAL MODEL OF AUTISTIC SPECTRUM DISORDER DUE TO CHANGES IN NEUROGENESIS? Hirst JBF, School of Biomedical Sciences, Medical School, Queen’s Medical Centre, Nottingham NG7 2UH [email protected] Shelley S(1), Damany M(1), Mediratta N(1), Hodgkinson C(1), Roope E(1), Fone K(1), Ebling F(1), Wigmore P(1) (1) School of Biomedical Sciences, Univ of Nottingham, Queens Medical Centre, Nottingham NG7 2UH

Background: Neurogenesis is the process of new neuron generation from neural stem and progenitor cells in the dentate gyrus of the hippocampus and sub-ventricular zone of adult mammalian brains. Alterations in neurogenesis can perturb development and lead to cognitive impairments, notably memory defi cits. Furthermore, changes in neurogenesis could contribute to some of the developmental and behavioural changes seen in autistic spectrum disorder (ASD). Previous rat studies show that prenatal exposure to the teratogen, sodium valproate, causes behavioural and anatomical changes with translational evidence to some core features of ASD. Moreover, exposure to valproate in adult rats’ results in decreases in neurogenesis associated with impaired memory and learning. Therefore, the current study investigates any relationship between learning and memory defi cits and neurogenesis following prenatal valproate exposure in rats. Methods: Pregnant Lister Hooded dams received sodium valproate (600mg/kg) or saline (1ml/kg s.c.) on gestation day 12.5. Behavioural tests were performed in resultant male and female offspring (n=8 in all four groups, Mohita et al., this meeting) including the two trial novel object discrimination (NOD; PND 39 with 2h inter-trial interval) to evaluate visual learning and memory. Rats were culled (PND 66), brains removed, frozen and coronal sections made to quantify changes in hippocampal volume (using cresyl violet staining and the Cavalieri’ equation) and Ki67 immunohistochemistry (a marker of cell division) to assess neurogenesis in the hippocampal dentate gyrus. Results: In the NOD test, female rats discriminated novel from familiar objects irrespective of prenatal treatment, while only males from saline treated dams were unable to discriminate such that there was a treatment x gender interaction (2way ANOVA F(3,28)=3.721, P=0.0227). There was no signifi cant difference in hippocampal volume irrespective of gender or prenatal treatment. There was no signifi cant difference in the number of Ki67 positive cells, suggesting no change in neurogenesis occurred after prenatal exposure to valproate. Conclusions: Prenatal exposure to valproate impaired visual learning and memory only in male rat offspring. However, this was not accompanied by any signifi cant change in hippocampal volume or neurogenesis, so the cause of this memory impairment is unclear. It is also interesting to note that the male offspring were more susceptible to the teratogenic effects of valproate, mirroring the male dominance of ASD in humans. Further studies are warranted to evaluate this as an animal model of ASD.

TD03

AN ANIMAL MODEL FOR THE FETAL VALPROATE SYNDROME – WITH RELEVANCE TO AUTISM Bertelsen F, CFIN Aarhus Univ, Nørrebrogade 44 Building 10G, 6th fl oor 8000 Aarhus C, Denmark [email protected] Møller A (1,2), Landau AM (1) Scheel-Kruger J (1) (1) CFIN, Aarhus Univ, Nørrebrogade 44, 10G, 8000 Aarhus, Denmark (2) PET-centre, Aarhus Univ Hospital, Nørrebrogade 44, 10G, 8000 Aarhus, Denmark

BACKGROUND: Our group has recently found that the prenatal administration of the antiepileptic drug valproate (VPA) to rats results in a signifi cantly enhanced number of neocortical cells. In the human clinic, the resulting fetal valproic acid syndrome is characterized by somatic malformations and cognitive dysfunctions, which may include the autistic spectrum disorders. AIM: The aim of this study is to develop a novel rodent model for autism induced by daily prenatal administration of valproate to pregnant rats. MATERIAL AND METHODS: Eighteen pregnant rats were exposed to daily, clinically relevant doses of VPA (20 and 100mg/kg) from the 12th day of pregnancy until birth. By using stereology and investigating the presence of biomarkers, we studied the neuropathological changes in the offspring of VPA-treated rats. In several behavioural tests of juvenile play, social interaction and novel object recognition, behavioural changes relevant to autism were evaluated. RESULTS: We have found that the offspring of VPA-treated rats demonstrate a signifi cant increase in the number of neocortical cells compared to control rats. Furthermore, these rats performed better in the novel object recognition test than did controls. Results from social interaction and juvenile play behaviour tests are currently under analysis. DISCUSSION AND PERSPECTIVES: The combination of behavioural and histological studies is necessary in the characterization and development of a novel model of autism. Our model differs from the original VPA model in which only a single high dose of VPA (600mg/kg) is injected at day 12.5 of pregnancy. We injected clinically relevant and much lower chronic doses of VPA in order to simulate the conditions in the clinic, where VPA administration to epileptic pregnant women increases incidence of autism and/or epilepsy in their offspring. Our increased cell number fi nding is consistent with the results of Courchesne et al (Courchesne E, et al. Neuron number and size in pre- frontal cortex of children with autism. JAMA. 2011;306(18):2001-2010), reporting an abnormal excess number of neurons in the prefrontal cortex of autistic males. A valid animal model may result in a better understanding of the developmental changes occurring during pregnancy and leading to autism in the human condition. Furthermore an animal model is the fi rst step in the testing of new pharmacological treatments of autism. ABSTRACTS A57

TD04

CLASS I HISTONE DEACETYLASE INHIBITION AMELIORATES SOCIAL COGNITION AND CELL ADHESION MOLECULE PLASTICITY DEFICITS IN A RODENT MODEL OF AUTISM SPECTRUM DISORDERS Regan CM, School of Biomolecular and Biomedical Science, UCD Conway Institute, Univ College Dublin, Dublin 4, Ireland 0004, [email protected] Foley AF, Gannon S, Rombach-Mullan N, Prendergast A, Barry C, Cassidy AW, Berand Neuropharmacology, NovaUCD, Belfi eld Innovation Park Univ College Dublin, Dublin 4, Ireland.

In utero exposure of rodents to valproic acid (VPA) is proposed to induce an adult behavioural phenotype with characteristics of autism spectrum disorders (ASD). We evaluated this model in terms of social cognition defi cits, a major core symptom of ASD. All procedures were approved by the UCD Animal Research Ethics Committee according to EU Council Directive 86–609–EEC and performed by individuals licensed by the Department of Health. In the social approach avoidance paradigm, a measure of social reciprocity, VPA-treated animals avoided the stimulus rat and spent the majority of time in the non-social chamber (F[2,23]=11.55; p=0.0004; p=0.0281; Mann-Whitney U-test). We further probed this anomalous affi liative behaviour by determining the ability of VPA-treated animals to process perceptual stimuli by orienting towards point light displays of biological motion using a touch-screen cognition testing protocol. Animals with prior in utero VPA exposure exhibited a constant performance over the 5 training sessions however their fraction of correct choice of the biologically relevant stimulus was signifi cantly lower than that observed in the control animals (F[1,90]=27.04; p<0.0001). As biological motion defi cits in ASD are associated with dorsal stream of cognitive processing, we further determined if animals with prior in utero exposure to VPA were impaired in the water maze spatial learning paradigm depending on the dorsal hippocampus. Animals administered VPA in utero were signifi cantly slower to locate the target platform across all four training sessions (F[1,56]=18.15; p<0.0001) and retention of platform position was just above chance level in the 24 hour probe trial. Learning-associated neuroplasticity, the ability to activate neural cell adhesion molecule polysialylation state (NCAM PSA) in the hippocampal dentate gyrus, was also signifi cantly impaired (p<0.05; Student t-test) following exposure to VPA. Given the evidence of dysregulation of epigenesis in ASD, we determined the consequence of chronic histone deacetylase (HDAC) inhibition with SAHA (5 mg/kg, i.p., 8 days), a pan-specifi c inhibitor, and MS-275 (1 mg/kg, i.p., 8 days), HDAC1-3 isoforms inhibitor, prior to the behavioural analyses. Both HDAC inhibitors ameliorated the defi cits observed in the social avoidance paradigm (SAHA: F[2,17]=60; p<0.0001; MS-275: F[2,17]=52.7; p<0.0001), the detection of biological motion (SAHA: F[1,90]=4.35; p=0.0399), spatial learning (SAHA: (F[1,56]=25.44; MS-275: F[1,56]=45.93; p<0.0001) and activation of NCAM PSA (MS-275: p<0.05, Student t-test). We conclude that in utero exposure to VPA provides a robust animal model for the social cognitive defi cits of ASD and a potential screen for developing novel therapeutics. This work was funded by Berand Ltd.

TD05

EFFECTS OF SELECTIVE NICOTINIC AGONISTS IN TWO COGNITIVE DOMAINS AND IN TWO MODELS OF COGNITIVE IMPAIRMENT IN FEMALE RATS: RELEVANCE FOR IMPROVING TREATMENT OF SCHIZOPHRENIA AND ALZHEIMER’S DISEASE McLean SL, b-neuro, Univ of Bradford, Richmond Road, Bradford, West Yorkshire BD7 1DP [email protected] Idris NF(1), Marsh S(1), Zarroug SHO(1), Grayson(1), Harte MK(1), Neill JC(1) (1) b-neuro, Univ Bradford, Richmond Road, Bradford, BD7 1DP

Introduction: Cognitive dysfunction remains a clinical unmet need in a range of neurodegenerative and psychiatric illnesses. The α7 and α4β2 subtypes of nicotinic acetylcholine receptors (nAChR) are involved in cognitive processing. The aim of this study was to compare the effi cacy of the selective α7 nAChR agonist, PNU- 282987, and the α4β2 nAChR agonist, RJR-2403, in two domains, in two models of cognitive impairment; sub-chronic PCP-induced reversal learning defi cits and delay dependent object recognition memory defi cits. Methods: 30 drug-naive adult female hooded-Lister rats received PNU-282987 (5, 10 mg/kg; s.c.), RJR-2403 (0.1, 1 mg/ kg; s.c.) or vehicle and were tested in the novel object recognition task following a 6 hour inter-trial interval (ITI). 50 rats trained to criterion in the reversal learning task received sub-chronic PCP (2 mg/kg) or vehicle i.p. twice daily for seven days, followed by 7 days washout. PCP-treated rats then received risperidone (0.1 mg/kg; i.p.), PNU-282987 (10 mg/kg), RJR-2403 (0.1 mg/kg) or vehicle and were tested in the 4 stage reversal learning task 30-60 min later. Data were analysed using paired t-tests and one-way ANOVA followed by post-hoc LSD t-test. Results: In the NOR task, vehicle treated rats were unable to discriminate between the novel and familiar object following a 6 hour ITI. This defi cit was attenuated by PNU-282987 (10 mg/kg) and RJR-2403 (0.1 mg/kg) (both P<0.05). Sub-chronic PCP produced a signifi cant defi cit in reversal learning in each of the 4 reversal stages (P<0.01-P<0.001). This defi cit was attenuated in reversals 1 and 2 by risperidone (P<0.01) and PNU-282987 (P<0.01), and in reversal 1 only by RJR-2403 (P<0.05). Conclusions: These data demonstrate the effi cacy of α7 and α4β2 nAChR agonists in two cognitive domains in two different animal models of cognitive impairment and reveals enhanced effi cacy of PNU-282987 in the 4 stage reversal learning test. Importantly, risperidone was found to reverse the sub-chronic PCP defi cit in reversal learning, but not the defi cit in delay dependent object recognition, whereas standard cognitive enhancers did (McLean et al., 2011, J. Psychopharmacology, 25 (8) Suppl, A27). This demonstrates that the sub-chronic PCP model detects compounds with effi cacy for cognition in schizophrenia, while the delay dependent NOR test may be more appropriate for detecting targets with effi cacy for cognition in other disorders. In summary, activation of α7 and α4β2 nACh receptors could be an important target for improving cognition in diseases such as schizophrenia and Alzheimer’s disease, which may be explored using these animal models. This work was funded by b-neuro.

TD06

THE EFFECT OF MEMANTINE ON REPETITIVE BEHAVIOURS IN THE TG2576 MOUSE MODEL OF ALZHEIMER’S DISEASE Middleton LJ, Psychology, Cardiff Univ, Tower Building 70 Park Place Cardiff CF10 3AT [email protected] Good, MA (1) (1) School of Psychology, Cardiff Univ, Tower building, 70 Park Place, Cardiff CF10 3AT

Repetitive behaviours represent one of the most burdensome cognitive defi cits in Alzheimer’s disease (Coen et al., 2001), yet the synaptic correlates behind this behaviour are unknown. Memantine is currently approved for the treatment of moderate to severe AD, and it is thought that its antagonistic effect on the n-methyl-d-aspartate (NMDA) receptor stops the excessive and pathogenic activation of these receptors that occurs in AD (Alberdi et al., 2010), reducing Ca2+ dys-regulation, excito-toxicity and cell death, thus preserving cognitive function. A transgenic animal model commonly used in AD research is the Tg2576 mouse model, which expresses the Swedish autosomal dominant amyloid precursor protein double mutation, resulting in elevated brain levels of A-β1-40 and A-β1-42, which correlate with cognitive defi cits in a number of behavioural tasks (Chapman et al., 1999). Using a within subjects design with the Tg2576 model, we showed that memantine (30mg/kg/day) reduced repetitive errors in a novel behavioural task that is sensitive to the perseverative behaviours seen in these mice. In the foraging task, a measure of spatial working memory, a one way repeated measures ANOVA was used to show a reduction in consecutive errors, but not total number of errors, in response to memantine administration (F(1, 7)=6.024, p≤0.05); this reduction in consecutive error rate was presently reversed with drug washout (F(1,7)=5.373, p≤0.05) and then re-instated with re-administration of the drug (F(1,7)=13.031, p≤0.05). No effect was seen in wild types on memantine. The next line of enquiry is to see if memantine has any effect on transgenic and wild type probabilistic reversal learning, using a spatial discrimination task where the ‘correct’ choice is reinforced the majority of the time e.g. 80% of the time, and not reinforced for the remaining 20% of trials, in an unpredicted manner. This task is a measure of cognitive fl exibility and perseverative behaviour (Amodeo et al., 2012). Based on our results from the foraging task, we would expect to see a reduction in consecutive errors in the probabilistic learning task. From these results we may conclude that NMDA receptor over-activation contributes to the repetitive behaviours seen in the Tg2576 model of AD, and must consider the implications of this for other neuropsychiatric diseases, such as OCD and autism, that have a pathological repetitive behavioural component. This work has been funded by a Knowledge Economy Skills Scholarship in collaboration with Cultech Limited. A58 ABSTRACTS

TD07

EFFECT OF AN OREXIN-1 RECEPTOR ANTAGONIST ON PROGRESSIVE-RATIO SCHEDULE PERFORMANCE: EVIDENCE FOR AN INVOLVEMENT OF OREXIN-1 RECEPTORS IN THE REGULATION OF INCENTIVE VALUE Olarte-Sánchez CM, Div of Psychiatry, Univ of Nottingham, B109 Medical School, Queen’s Medical Centre, Nottingham NG7 2UH [email protected] Valencia-Torres L(1), Body S(1), Cassaday(2), Bradshaw CM (1), Szabadi E(1) (1) Div Psychiatry, Univ Nottingham, Queen’s Medical Centre, Nottingham NG7 2UH (2) Sch Psychology, Univ Nottingham, University Park, Nottingham NG7 2RD

The orexins are neuropeptides synthesised in hypothalamic nuclei. It has been suggested that a sub-population of orexinergic neurones whose somata lie in the lateral hypothalamic area (LHA) play a specifi c role in regulating the reinforcing effi cacy of food and drugs [Harris and Aston-Jones, 2007, Trends Neurosci 29:571-577]. We examined the effect of the orexin-1 receptor (OX1R) antagonist SB-334867-A (1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride) on performance on the progressive-ratio (PR) schedule of reinforcement, in which the response requirement increases progressively for successive reinforcers. The data were analysed using a mathematical model which yields a quantitative index of reinforcer value and dissociates effects of interventions on motor and motivational processes [Killeen, 1994, Behav. Brain Sci. 17:105-172]. According to this model, response rate, R, is related to ratio size, N, according to a bitonic function (R = [1-(1-β)^N]/δ – N/a). The peak of the function (1/δ: maximum response rate), is regarded as an index of motor performance, whereas the slope of the descending limb refl ects the incentive value of the reinforcer, a (slope = -1/a) [Bezzina et al., 2008, Psychopharmacology, 197:339-350]. Rats were trained under a PR schedule using food-pellet reinforcement for >90 daily sessions before undergoing treatments. Killeen’s equation was fi tted to the data from each rat and the parameters were derived for each treatment condition. A criterion of p<0.05 was used in all comparisons. Experiment 1. Ten rats received SB-334867-A 20 mg kg-1 and vehicle intraperitoneally 30 min before testing. SB-334867-A signifi cantly reduced a [s: vehicle, 120.6±11.8; SB-334867-A, 73.7±14.0; t(9)=3.4] and increased δ [s: vehicle, 0.70±0.06; SB-334867-A, 0.89±0.11; t(9)=2.3]. Experiment 2. Under general anaesthesia, 21 rats received unilateral lesions of the LHA with the neurotoxin orexin-B-saporin (OxSap), followed by bilateral cannula implantation in the nucleus accumbens shell (AcbS), a region rich in OX1R. After recovery from surgery, they received injections of SB-334867-A 6 ng in 0.5 μl 0.9% NaCl into the AcbS contralateral (n=10) or ipsilateral (n=11) to the lesion 15 min before testing. SB-334867-A induced a signifi cant reduction of a in the contralateral group [s: contralateral, -56.0±25.6; ipsilateral, +15.3.±21.3; t(19)=2.2]. The effect of SB-334867-A on δ did not differ between the groups [t(19)=1.2] The results are consistent with the hypothesis that orexinergic neurotransmission mediated by OX1R contributes to the regulation of the incentive value of reinforcers [Thompson and Borgland, 2011, Behav. Brain Res. 217:447-453], and implicate the orexinergic projection from the LHA to the AcbS in this process. Funded by the University of Nottingham

TD08

EARLY MARKERS OF COGNITIVE ENHANCEMENT: DEVELOPING AN IMPLICIT MEASURE OF COGNITIVE PERFORMANCE Pringle A, Psychiatry, Univ of Oxford, Warneford Hospital, Oxford OX3 7JX [email protected] Browning M (1) Parsons E (2) Cowen PJ (2) Harmer CJ (2) (1) fMRIB Centre, Univ of Oxford, John Radcliffe Hospital, Oxford, OX3 7DU (2) Dept of Psychiatry, Univ of Oxford, Warenford Hospital, Oxford, OX3 7JX

The potential for cognitive enhancement has generated a great deal of interest, not only for those suffering from disorder induced defi cits, but also for healthy individuals. However, currently available cognitive enhancers appear to be limited to relatively modest overall effects, and developing effective cognitive enhancers is therefore an ongoing aim of the pharmaceutical industry. A limiting factor in the development of such drugs has been uncertainty about the best way to measure increments in cognitive performance [Husain M. & Mehta M. (2011) Trends in Cognitive Sciences, 15, 28-36]. Healthy volunteer models may represent a useful way to assess candidate compounds; such models are often limited, however, by ceiling effects in performance on cognitive tasks. The aim of the present study was therefore to develop a measure of cognition relevant to the action of candidate cognitive enhancers which might be sensitive to pharmacological manipulation in healthy volunteers. Healthy volunteers (n=34) were randomised to receive a single dose of modafi nil (100 mg) or placebo. Five hours post dose volunteers were assessed using a novel compound learning task which is a measure of attentional fl exibility in learning developed using an amalgam of the intradimensional/extradimensional set-shifting and visual probe tasks. Volunteers also completed an auditory digit span task. Visual analogue scales (VAS) were given before and 5 hours after dosing. Modafi nil increased alertness as measured by the VAS (<0.01). In the compound learning task, modafi nil enhanced accuracy for the predictive compared to the non-predictive stimulus across all blocks of the task (p<0.05). Reaction time measures revealed that learning was specifi cally enhanced by modafi nil in the extradimensional shift block (p<0.05). There was no effect of modafi nil on the auditory digit span task. The current study aimed to explore the potential of an implicit measure of attentional fl exibility to capture cognitive enhancing properties of pharmacological agents. The results suggest that the implicit compound learning task is sensitive to acute low dose modafi nil administration in healthy volunteers even in the absence of changes in conventional measures such as the digit span task. Taken together, this implies that the compound learning task shows promise as a measure of cognitive function that maybe sensitive to drug-induced changes, and which shows the potential to be more sensitive than conventional cognitive measures This study was funded by the MRC: G0801432/1 ABSTRACTS A59

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THE ROLE OF SEROTONIN IN DECISION-MAKING AS SHOWN BY PET Faulkner P, Inst of Cognitive Neuroscience, Univ College London, Alexandra House, 17 Queen Square, London WC1N 3AR [email protected] Selvaraj, S (1), Huys, Q (2), Pine, A (3), Howes, O (1), Roiser, P (4) (1) Cyclotron Building, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN (2) Gatsby Computational Neuroscience Unit, Alexandra House, 17 Queen Square, London, WC1N 3AR (3) Clinical Psychopharmacology Unit, Department of Clinical, Educational and Health Psychology, University College London, Gower Street, London, WC1E 6BT (4) Institute of Cognitive Neuroscience, Alexandra House, 17 Queen Square, London, WC1N 3AR

The serotonin (5-HT) system has been suggested to be involved in a number of cognitive processes, including decision-making. A key component of the 5-HT system is the 5-HT1A autoreceptor, which controls 5-HT release by inhibiting the fi ring of serotonergic neurons via a feedback loop. The aim of this study was to assess whether individual variability in 5HT¬1A receptor density and 5-HT release were correlated with decision-making cognition. We used a novel positron emission tomography (PET) approach to study serotonin release, employing a partial agonist, 11C-CUMI, to measure 5-HT release, much in the same way that raclopride allows the measurement of dopamine release. Fifteen healthy volunteers completed three behavioural tasks in which performance was hypothesized to be infl uenced by 5-HT. The fi rst of these tasks was a sequential decision-making task that allowed the observation of participant’s tendency to “prune” away more negative options from a tree of possible decisions (Huys et al, 2012. PLoS Computational Biology, 8, 3). The second task involved choosing between two gambles, each of which consisted of differing probabilities of winning or losing varying amounts of money (Rogers et al, 2003. Neuropsychopharmacology, 28, 153-162). The third task was a temporal discounting task, asking subjects to choose between a smaller, more immediate reward, and a larger, more delayed reward (Pine et al, 2009. Journal of Neuroscience, 29(30), 9575-9581). Of these participants, all fi fteen had previously undergone a PET scan in which they received an injection of 11C-CUMI before a placebo, with thirteen also undergoing a PET scan in which they received an injection of 11C-CUMI before citalopram. Results of the PET scans revealed that, contrary to expectation, administration of citalopram induced an increase in 5-HT1A receptor binding (suggestive of decreased 5-HT release) in the ACC and insula, as well as the hippocampal complex, and frontal, temporal and parietal lobes. Participants’ scores from each of the behavioural tasks were entered as second-level covariates in voxel-wise analyses including 1) their placebo PET images and 2) their difference images (computed as the placebo minus the citalopram image). These analyses yielded correlations between their behaviour and baseline 5-HT1A binding, and their behaviour and the change in 5-HT-1A binding (and thus 5-HT release) due to citalopram infusion, respectively. There were signifi cant correlations between decision-making processes and baseline/change in 5-HT1A receptor binding values in regions including the midbrain, hippocampus, frontal and temporal lobes. These data highlight the importance of 5-HT transmission in human decision-making. Financial sponsorship from the Medical Research Council.

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SCOPOLAMINE INFLUENCES ON BRAIN ACTIVITY DURING PAIRED ASSOCIATES LEARNING: A MULTIVARIATE APPROACH Joules R, Center for Neuroimaging Science, Inst of Psychiatry, Kings College London, DeCrespigny Park, Denmark Hill, London SE5 8AF [email protected] Marquand AF(1), Doyle OM (1), Mehta MA(1) (1) Dept of Neuroimaging, Centre for Neuroimaging Sciences Po89, Inst of Psychiatry, King’s College London, London UK SE5 8AF;

Introduction: Scopolamine is a muscarinic receptor antagonist, which impairs a range of cognitive functions thought to resemble impairments seen in Alzheimer’s disease. It used to model defi cits related to cholinergic dysfunction and to screen novel compounds. Neuroimaging studies have demonstrated reduced hippocampal activity during encoding following scopolamine compared to placebo. Given the widespread cholinergic projections in the brain, we predicted a distributed pattern of changes would be able to capture the effects of scopolamine on a memory task. Methods: 16 healthy volunteers were scanned using BOLD fMRI (TR=3000ms; TE=40ms) within a double- blind, placebo-controlled cross-over design. Scopolamine (s.c. 0.2mg) was administered 90 minutes before scanning with a paired associates learning task. Participants were required to encode and retrieve visuo-spatial associations over three consecutive phases. For each experimental phase, participants encoded six different stimuli in different locations, subsequently retrieving the same stimuli using a joystick; each phase was repeated three times. A control block where all six stimuli were identical (i.e. no encoding) was interleaved with each learning block. Data were pre-processed in SPM5. The outputs from a moving-average of TR=2 across the three phases and the control block, (39 outputs) were used to train 39 Gaussian process classifi ers using leave one out cross validation. Results: Participants showed improved performance accuracy over learning phases I-III. Scopolamine impaired performance during phases II and III. There were three peaks of high classifi cation accuracy corresponding to encoding (phase II, 81%), mid-retrieval (phase II, 81%) and late-retrieval (phase I, 78%); p<0.01 corrected for multiple comparisons. Here we focus on encoding. While all regions contributed to the Gaussian process classifi cation accuracy the following regions were highly weighted in favour of scopolamine: the medial prefrontal cortex extending orbitally, basal ganglia, lateral thalamus and left hippocampus, corresponding to increased activity on scopolamine. The highest weights favouring placebo included the medial thalamus, occipital lobes and right parahippocampal gyrus. While these components were prominent they should be considered within the contect of the resultant whole brain pattern. Reasonable classifi cation accuracies were achieved for the control blocks; these did not survive multiple comparisons correction. Discussion: Scopolamine impaired visuo-spatial conditional associative learning and altered the BOLD response during both encoding and retrieval in distributed brain regions extending beyond the medial temporal lobes. The best classifi cation during encoding was achieved in the middle phase of learning indicating a particular role for the cholinergic system when encoding is minimally coloured by novelty or familiarity. Overall, this study shows the power of combining a moving-average window with multivariate pattern analysis to determine temporally-specifi c distributed effects of drugs. Acknowledgements: This work was funded by a studentship from the European Commission as part of the Innovative Medicines Initiative. A60 ABSTRACTS

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A COMPARATIVE STUDY OF THE EFFECTS OF NEONATAL EXPOSURE TO CLOMIPRAMINE, AMITRIPTYLINE AND FLUOXETINE ON BEHAVIOUR IN LATER LIFE IN AN ANIMAL MODEL O’Brien S, Pharmacology and Therapeutics, NUI, Galway [email protected] Amchova, P. (1,2), Bannerton, K. (1), Cormican, D. (1), Osikoya, A.S. (1), Kelly, J.P. (1) (1) Pharmacology and Therapeutics, NUI, Galway (2) Dept of Pharmacology, Faculty of Medicine, Masaryk Univ, Czech Republic

In humans, prenatal antidepressant exposure has been associated with behavioural defi cits in the neonatal period. However, controlled studies into the long-term effects of this exposure are not logistically or ethically possible and so animal models are proposed as a viable alternative. Previous work in our laboratory has found that early life exposure to amitriptyline and fl uoxetine via maternal transfer led to abnormalities in locomotor activity and anxiety-like behaviour at different ages in adulthood in the offspring (O’Brien, S., Kelly, J.P., 2010, Journal of Psychopharmacology, 24 S3:A38; O’Brien, S., Kelly, J.P., 2011, Journal of Psychopharmacology, 25 S8:A24). The present study is an extension of this work, investigating the behavioural effects in adulthood of animals treated with clomipramine, amitriptyline and fl uoxetine from post-natal day (PND) 8-21, which corresponds to the third trimester of human pregnancy. Male and female Sprague-Dawley rats were treated daily with vehicle (saline), fl uoxetine (10mg/kg), amitriptyline (10mg/kg) or clomipramine (20mg/kg) from PND8-21 (n=16 of each sex per group, all drugs administered subcutaneously). In adulthood, the animals were divided into two equal groups and locomotor activity in the open fi eld (OF) and anxiety-like behaviour in the elevated plus maze (EPM) were measured at either PND56 or PND84. Body weight was measured at PND8, 21, 56 and 84 also. All data were analysed using Two-Way ANOVAs accompanied by appropriate post-hoc tests, and p<0.05 was deemed statistically signifi cant. No effects of any drug were found on locomotor activity in the OF at either age or on anxiety- like behaviours in the EPM at PND84. A drug effect was found in the EPM at PND56, with clomipramine-treated animals spending more time in the open arms of the maze than vehicle-treated animals, thus displaying a reduction in anxiety-like behaviour (F3,56=5.982, p≤0.001). There were no differences in body weight at PND8 (i.e. prior to commencement of dosing), but all drug treatments led to a reduction in body weight at PND21 when compared with the vehicle group (F3,124=19.194, p<0.001). Such differences were not apparent at either testing point in adulthood. It can be concluded that neonatal treatment with the antidepressants amitriptyline and fl uoxetine, at the doses used in the present study, had no effects on adult locomotor activity or anxiety-like behaviour. Clomipramine may have some effects on anxiety-like behaviour, although these effects are age-dependent. Further studies employing a range of doses may be necessary to determine if these drugs are capable of inducing changes in adult behaviour. Research supported by the College of Science Fellowship, NUI,Galway

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A NEW COMPUTER PROGRAM UNDER DEVELOPMENT FOR SCORING AND PROCESSING BEHAVIOURAL DATA Kokras N, Dept of Pharmacology, Medical School, Univ of Athens, 75 Mikras Asias st, Athens, Greece 11527 [email protected] Theocharis F(1), Kafetzopoulos V(1), Papadopoulou-Daifoti Z(1), Dalla C(1), Baltas D(1) (1) Dept of Pharmacology, Medical School, Univ of Athens, Athens, Greece

Behavioural analysis in preclinical neuropsychopharmacology relies in the accurate measurement of animal behaviour. Advances in computer science allowed the development of elaborate software which records animal behaviour often with a high degree of automatism taking advantage of artifi cial intelligence and image tracking technologies. However, those commercial software solutions have a high purchasing cost and although they rely on advanced algorithms sometimes they do not provide as detailed and accurate assessment of animal behaviour as human observation does. The objective of this project was to develop a versatile and expandable software package for manual scoring and data processing of behavioural pharmacology experiments. The program is developed in Visual C# and is compatible with personal computers able to run MS WindowsXP © or later operating system versions with the .NET 4.0 extensions. All data are stored in a relational database compatible with different engines (SQLite, MySql, MS-SQL, Oracle, etc). It is released under the Creative Commons license, freely available to the academic community. Although the program is in its fi rst alpha versions and under active development, it is used in the Department of Pharmacology for registering and analysing behavioural experiments such as the Forced Swim Test and the Elevated Plus Maze. The graphical interface is organized around user-defi ned projects, which may contain one or more behavioural tests. The researcher defi nes experimental groups and subjects within the projects and thus a complete user-manageable record of all behavioural data is stored in the local database. Upon launching the behavioural registration routine, customizable key codes allow the registration of state and instant behaviours at their time of appearance. Following completion of the session, the processing of data allows calculation of several parameters, such as duration of behaviour or its latency to appear as well as time and sequential analyses. Output fi les can easily be imported to any spreadsheet program for further analysis. In addition, a high-quality representation of the recorded behaviours over time can be exported in a graphical format for further use. Accurate behavioural analysis remains of paramount importance in preclinical psychopharmacology and the deployment of this new, modern software platform signifi cantly increased productivity without imposing the heavy burden of cost associated with available commercial solutions. Continuous further development is scheduled and suggestions for future improvements are most welcomed. Sources of Financial Sponsorship: None

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PHENOTYPIC STUDIES ON CONDITIONAL MUTANT MICE WITH PROGRESSIVE LOSS OF DRD1A CELLS IN RELATION TO HUNTINGTON’S DISEASE O’Leary C, (1)Molecular & Cellular Therapeutics (2)Florey Neurosci Inst (1)Royal College of Surgeons in Ireland (2)Univ of Melbourne, (1)123 St Stephens Green, Dublin (2)Melbourne Australia, Dublin 2, [email protected] Massalas J(2), Waddington JL(1), Drago J(2). (1)Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin; (2)Florey Neurosci Inst, Univ of Melbourne, Melbourne, Australia.

Huntington’s disease (HD) is an autosomal dominant disorder caused by mutation in the huntingtin gene and characterised by expanded CAG repeats. HD causes progressive neurodegeneration, initially in the striatum but then extending to other areas, particularly the cortex. Patients experience motor, cognitive and behavioural defi cits. Some aspects of the disease can be manifested outside the CNS, including weight loss and muscle wasting. The dopaminergic system is important in HD due to its role in movement, memory and psychopathology. Of the fi ve dopamine receptor subtypes, D1 (Drd1a) is progressively lost from the cortex and striatum in HD. To clarify these aspects of HD pathophysiology, three conditional mutant mouse lines have been constructed, using cre/lox technology and regionally specifi c promoters, to evidence progressive loss of Drd1a-expressing cells from the striatum (DARPP-32/Cre D1 Tox), cortex (Emx/Cre D1 Tox) and both the striatum and cortex (CamKIIa/ Cre D1 Tox). As HD is progressive, behavioural phenotyping was performed in two cohorts: at 20 weeks and 20 months. Several levels of phenotypic assessment were preformed. All data were analyzed using parametric analysis of variance (ANOVA), followed by Fisher’s Least Signifi cant Difference (LSD) post hoc comparisons. Body weight was reduced in the aged DARPP-32/Cre D1 Tox (striatal) and CamKIIa/Cre D1 Tox (cortical + striatal) lines (P < 0.05). The DARPP-32/Cre D1 Tox (striatal) line developed tic-like jerks that were suppressed by the dopamine antagonist haloperidol and Parkinsonian motor defi cits including locomotor slowing, ataxia and a chaotic gait patter, a cluster of phenotypic features seen in the Westphal HD variant, i.e. rare, juvenile onset HD. This phenotype can be attributed to Drd1a cell loss in the striatum. Spatial working memory was impaired in the CamKIIa/Cre D1 Tox (cortical + striatal) aged cohort (P < 0.05). Social novelty preference was disrupted in both the Emx/Cre D1 Tox (cortical) and CamKIIa/Cre D1 Tox (cortical + striatal) lines (P < 0.05); these effects were only observed in the aged cohort and can be attributed to progressive loss of Drd1a cells from the cortex. These novel conditional mutants with regionally specifi c, progressive Drd1a loss are critical tools for understanding the pathophysiology and functional impairments of HD. These studies were supported by Science Foundation Ireland and the RCSI Alumni fund and the Australian National Health & Medical Research Council. ABSTRACTS A61

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INVESTIGATING THE ROLE OF MGLU2 RECEPTORS IN DOI-INDUCED HEAD-TWITCH RESPONSES USING A WISTAR RAT STRAIN LACKING MGLU2 EXPRESSION Wood CM, School of Physiology and Pharmacology, Univ of Bristol, D7a, School of Medical Sci, University Walk, Bristol BS8 1TD [email protected] Mitchell EN(1), Lodge D(1),Robinson ES(1), (1) School of Phys & Pharm, School of Med Sciences, Bristol, BS8 1TD

Group II metabotropic glutamate receptors are considered to be important in multiple psychiatric disorders. Recent work has highlighted the importance of the mGlu2 receptor on the behavioural effects of hallucinogenic 5HT2A agonists, such as LSD and DOI, through a heterodimeric G-protein coupled receptor complex (Moreno et al., 2011; Neuroscience Letters 493: 76–79). A failure to express the mGlu2 receptor in the UoB Han Wistar (formerly B&K Wistar rats; UoB:Wi) rat strain has been reported recently (Ceolin et al., 2011; J Neuroscience 31: 6721–6731). This study aimed to investigate how the loss of mGlu2 receptor expression alters the stereotypic head-twitch behaviour in these rats following DOI treatment. Eighteen age and weight-matched Charles River control (CR:Wi; n=9) and UoB:Wi (n=9) rats were used from an in-bred University of Bristol colony previously described by Ceolin et al. (2011). Head-twitch behaviour was scored manually in DOI (1 and 3mg/kg, i.p.) and vehicle treated animals for 30 minutes, immediately following administration. Scoring was carried out by individuals blind to strain and treatment. The study was fully randomised using a Latin square design, with 7 days washout between treatments. A two-way ANOVA revealed a statistically signifi cant effect of treatment (F(2,32)=116.85, p<0.001) and interaction between treatment and genotype (F(2,32)=4.581, p=0.02). DOI induced a highly-signifi cant (p<0.001) increase in head-twitches in both CR:Wi and UoB:Wi rats at both dose concentrations compared to vehicle treated animals. Genotype comparisons highlighted a signifi cant reduction in head-twitch responses at 3mg/kg (p=0.014) but not at 1mg/kg (p=0.286) in the UoB:Wi rats compared to CR:Wi rats. This study has shown that Wistar rat substrains with different levels of mGlu2 receptors both show a behavioural response following DOI administration. This suggests the mGlu2 receptor is not critical to this behavioural response, which is different to a previous report in mice (Moreno et al., 2011). However, the extent of the behavioural response is altered by mGlu2 expression as the UoB:Wi rats elicited signifi cantly lower head-twitch responses at the highest dose tested. Further pharmacological and molecular investigations are required to understand the role of mGlu2 in the behavioural effects of 5-HT2A agonists. ESJR is a senior lecturer at the University of Bristol; CMW is funded by a BBSRC CASE Studentship with Eli Lilly.

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NEURAL INFLAMMATION AND KYNURENINE PATHWAY: DIFFERENTIAL EFFECTS OF OMEGA-3 AND OMEGA-6 POLYUNSATURATED FATTY ACIDS Zunszain PA, Psychological Med, Inst of Psychiatry, King’s College London, 125 Coldhabour Lane, SE5 9NU [email protected] Su Y-P (1,2,3), Anacker C (1), Thuret S (1), Su K-P (1,2) and Pariante CM (1) (1) Inst of Psychiatry, King’s College London (2) Dept of Psychiatry and Mind-Body Interface Lab (MBI-Lab), Graduate Inst of Neural and Cognitive Sciences, China Medical Univy and Hospital, Taichung (3) Cathay General Hispital, Taipei

Infl ammatory processes have been implicated as playing an important role in the pathophysiology of major depression disorder. Treatment with antidepressants have been shown to attenuate some of these neuroinfl ammatory dysfunctions. In particular, omega-3 polyunsaturated fatty acids (PUFAs) have shown to have antidepressant effects, with evidence for the ratio of omega-3 to omega-6 being important. The aim of this study was to identify molecular mechanisms through which α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), stearidonic acid (SDA) and arachidonic acid (AA) modulate infl ammatory responses in human brain cells. We used a conditionally immortalized human hippocampal stem cell line (HPC03A/07, ReNeuron, UK) as a model. Cells were incubated for 24 hours with IL-1beta (10 ng/ml), which stimulates the production of IL-6. They were then co- or pre-treated with the different PUFAs. Measurement of IL-6 released into the supernatant was done by ELISA (R&D). Quantifi cation of mRNA expression of genes involved in the kynurenine pathway was performed by qPCR, using beta actin and GAPDH as housekeeping genes. The results of this study showed a reduction of the production of IL-6 induced by IL-1beta by ALA (- 35%, p < 0.001), EPA (- 31%, p < 0.001) and DHA (-28 %, p < 0.05). No signifi cant changes were detected for SDA or AA. Because EPA and DHA are frequently used in patient treatment, we further analysed their effects on the kynurenine pathway. DHA dose-dependently reduced levels of transcripts for indoleamine-2,3-dioxygenase (IDO), the enzyme that metabolizes tryptophan to kynurenine. No changes were observed for EPA. Furthermore, no signifi cant changes were observed in the levels of kynurenine-aminotransferase -1 (KAT1), the enzyme that regulates production of the potentially neuroprotective kynurenic acid. Our fi ndings provide further information on the pathways by which PUFAs regulate infl ammation and neurodegeneration processes in human brain cells.

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PROFOUND SUPPRESSION OF NORADRENALINE, DOPAMINE AND 5-HT TURNOVER IN VARIOUS REGIONS OF RAT BRAIN EVOKED BY THE α2-ADRENOCEPTOR AGONIST, CLONIDINE Heal DJ, RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF [email protected] Sood P (1), Prow M (1), Rowley H (1) (1) RenaSci Ltd, BioCity, Pennyfoot St, Notts NG1 1GF

Background: 3-Methoxy-4-hydroxyphenylglycol (MHPG) is a noradrenaline (NA) metabolite that has been validated as a marker of turnover in mouse brain (Heal et al., 1989, BJP 96:547), but not in rat brain where it exists predominantly as the sulphate conjugate. More recently, we have developed “neurochemical fi ngerprinting” in the mouse as a rapid ex vivo screen to identify compounds with different presynaptic dopaminergic mechanisms (Heal et al, 2009, 2010, SfN On line). We have now used, clonidine to determine whether unconjugated MHPG can be used as an indicator of NA turnover in the rat, and in addition, the neurochemical fi ngerprint of this α2 adrenoceptor (α2AR) agonist in the striatum and prefrontal cortex (PFC) Methods: Male Sprague Dawley rats (n=8/group) were dosed with clonidine (100μg/kg, ip) or saline and killed 60 min later. PFC, striatum (STR) and rest of brain minus cerebellum (RoB) were rapidly dissected and snap frozen in liquid N2. RoB was analysed for MHPG (Heal et al, 1989). PFC and striatum were analysed for monoamines (NA, DA, 5-HT) and metabolites (3 MT, DOPAC, HVA, 5 HIAA) by HPLC-ECD (Heal et al, 2009, 2010, 1990, Neuropharmacol 12:1141). Results: Clonidine decreased unconjugated MHPG (-49.8%, p < 0.001) and its effect was almost identical to the percentage reduction of total MHPG in mouse brain (Heal et al, 1989). In STR, clonidine decreased DA turnover as shown by falls in DOPAC (-21.5%, p<0.05), and 3MT (-79.3%, p<0.001), and an increase in the DA/DOPAC ratio (38.7%, p<0.001). In PFC, clonidine decreased DA and 5-HT turnover as respectively shown by increases in the ratios of DA/DOPAC (89.1%, p<0.05) and 5 HT/5HIAA (22.1%, p<0.01) and a decrease in 5 HIAA ( 16%, p<0.05). Clonidine also increased the neuronal concentration of NA (17.3%, p<0.001) and DA (67.5%, p<0.01). Conclusion: The results show clonidine decreases unconjugated MHPG indicating that this metabolite is a viable index of NA turnover in rat brain. They also reveal this α2AR agonist markedly suppresses turnover DA in PFC and STR and 5-HT in PFC. The observed increases in DA and NA are consistent with a decrease in the turnover of these catecholamines in PFC. Finally, these results provide preliminary support for the viability of neurochemical fi ngerprinting in rats. A62 ABSTRACTS

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A SINGLE DOSE OF FLUOXETINE MODULATES ANGER PROCESSING IN YOUNG HEALTHY VOLUNTEERS Capitão LP, Dept of Psychiatry, Univ of Oxford, Neurosciences Bldg Warneford Hospital Headington OX3 7JX [email protected] Murphy SE (1), Harmer CJ (1) (1) Dept of Psychiatry, Univ of Oxford, Warneford Hospital, OX3 7JX

The pharmacological treatment of adolescent depression is complex, and serotonergic antidepressants (SSRIs) other than fl uoxetine are not recommended for this disorder. Pre-clinical research suggests that antidepressant administration may have age-dependent outcomes (Homberg et al. 2011, PLoS ONE 6: e16646.), but there is a lack of human studies investigating the short- and long-term consequences of SSRIs in youth, as well as the differential mechanisms underlying antidepressant treatment in young vs. adult populations. Neuropsychological studies in adults suggest that SSRIs have early effects on emotional processing, even before therapeutic changes emerge (Browning et al. 2007, J Psychopharm 1: 684–690). This study therefore aims to investigate the acute effects of fl uoxetine in young people. Thirty-nine healthy volunteers (18 – 21 years) were randomised to receive a single oral dose of fl uoxetine (20 mg) or placebo. After 6 hours, the Facial Expression recognition Task (FERT) and the Emotion Potentiated Startle (EPS) were completed. In the FERT, subjects were asked to identify different facial expressions presented at different intensities. There was a signifi cant interaction between group (drug vs. placebo) and emotion with respect to reaction times [F(6,222)=2.792, p=0.024] and misclassifi cations [F(6,222)=4.348, p=0.009]. Participants on fl uoxetine were slower to identify anger (p=0.045), and misclassifi ed more faces as being neutral (p=0.012) and less as angry (p=0.020). There was also a trend for an interaction between group and accuracy [F(5,185)=2.204,p=0.097], with participants in the fl uoxetine group being less accurate to identify anger (p=0.019). In the EPS, eye-blink amplitudes were measured while subjects viewed neutral, negative and positive pictures, presented along with acoustic probes. A trend for an interaction between valence and group [F(2,52)=2.822, p=0.065] was found. Separate repeated measures ANOVAs showed a valence effect in the placebo group (p=0.015), refl ecting the usual potentiation of the startle response in the presence of negative pictures compared with positive and neutral, but there was no effect of valence in the fl uoxetine group (p=0.295). These results show that a single dose of fl uoxetine decreases negative bias in young volunteers, targeting specifi cally the processing of anger. This corroborates previous evidence that SSRIs have early effects consistent with antidepressant action and this effect on anger is particularly interesting given that irritable mood is a core symptom of adolescent depression, being the only diagnostic criterion that differentiates this disorder from adult depression. Fluoxetine also abolished the emotion potentiatiation of the startle in the presence of negative images, suggesting an anxiolytic-like mechanism. The student collecting the data is funded by the Portuguese Foundation for Science and Technology (FCT). and all research costs were covered by a Medical Research Council (MRC) grant. ABSTRACTS A63

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BEHAVIOURAL ANALYSIS OF A C-TERMINAL REGION DISC1 MUTANT MOUSE Dachtler J, Inst of Membrane and Systems Biology, Univ of Leeds, Garstang Bldg, Leeds LS2 9JT, UK [email protected] Rodgers RJ (1), Clapcote SJ (2) (1) Inst of Psychological Sciences, Univ of Leeds, Leeds, LS2 9JT, UK. (2) Inst of Membrane and Systems Biology, Garstang Building, Univ of Leeds, Leeds, LS2 9JT, UK.

Schizophrenia is associated with positive and negative symptoms, with a population incidence of ~1%. Genetic alterations have been associated as risk factors for developing the illness, yet the story is complex. Notwithstanding, DISC1 has become a leading candidate gene for schizophrenia. The full-length DISC1 protein (854aa) is predicted to consist of a globular N-terminal region (1–350aa) and an alpha-helical coiled–coil-containing C-terminal region (351–854aa). The C-terminal region contains ~80% of the DISC1 interaction partners. Within the C-terminal region, a risk polymorphism at S704C resulted in altered binding to NDE1 and NDEL1, while another study found that an inducible expression of DISC1 peptide spanning residues 671-852 impaired sociability and working memory in mice. Further work is needed to clarify the role that mutations within the C-terminal region may convey to schizophrenia-like phenotypes. We have employed an ENU-derived C-terminal region missense mutation (an aspartate was substituted for a glycine) at position 453 (human D456), backcrossed to a C57BL/6N background. This is within the region where a rare mutation (R418H) has been found in schizophrenia patients. We tested male and female DISC1 D453G mice (hereon in termed DISC1) and their wild-type littermates within a test battery. We found that in a 30 minute open fi eld test, female DISC1 mice (FDISC1) travelled further than female wild-type mice (FWT; p=0.001); spent less time immobile (p=0.001); spent more time closer to the arena walls (p<0.05) and less time in the centre of the arena (p=0.001). There were no differences between male wild-type and DISC1 mice. The elevated plus maze further suggested an anxiety phenotype, with FDISC1 spending less time in the open arms and centre compared to FWT (p=0.001 and p<0.05, respectively). A two-stage test of social interaction, fi rstly testing the preference for exploring an empty cage or a novel mouse, and then discriminating between a novel and a previously explored mouse, showed at both stages that FDISC1 mice spent less time exploring the novel mice than FWT (p=0.001 and p=0.005, respectively). No differences were found between male mice. Finally, FDISC1 mice were quicker to fl oat during the forced swim test (p<0.05). Together, our fi ndings reveal that our C-terminal region missense mutant mouse model refl ects some of the phenotypes associated with schizophrenia. We aim to continue to explore the synaptic mechanisms that could result in the observed behaviours, to determine the importance of the D453G mutant as a preclinical model. Supported by the MRC.

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MATERNAL IMMUNE ACTIVATION INDUCES EXECUTIVE DYSFUNCTION AND CHANGES IN GABAERGIC INTERNEURONES IN THE PREFRONTAL CORTEX Wallace J, Inst of Neuroscience, Newcastle Univ, The Medical School, Framlington Place, Newcastle-upon-Tyne NE2 4HH [email protected] McQuade R(1), Marston HM(2), Gartside SE(1) (1) Inst of Neuroscience, Newcastle Univ (2) TPP Global, 10 York Place, Edinburgh, Scotland, UK

Gestational infection is a recognised risk factor for schizophrenia in the offspring. Defi cits in executive function, as well as changes in GABAergic interneurones in the prefrontal cortex (PFC), have been identifi ed in patients with schizophrenia. Here we investigated the potential causal relationship between gestational infection (or maternal immune activation; MIA) and dysfunction of the prefrontal cortex (PFC). The structure and function of the PFC was assessed by investigating changes in parvalbumin (PV), calbindin (CB) and calretinin (CR) expressing GABAergic interneurones in the infralimbic (IL) and prelimbic (PL) cortices of the medial PFC (mPFC) and by the attentional set shifting task (ASST; a rat analogue of the human ID/ED test). Pregnant female Lister hooded rats were injected (i.v) on gestational day 15 with either saline vehicle (VEH) or the cytokine releaser Poly I:C (MIA). Male pups (n=12 per group) were allowed to mature until 3 months of age. Rats then underwent the ASST (a series of rewarded discriminations (simple (SD), compound (CD), reversal (REV1), intradimensional (ID), reversal (REV2), extradimensional (ED), reversal (REV3)). The following day animals were sacrifi ced and brain tissue was collected and processed for immunohistochemistry using antibodies against PV, CB and CR. Trials to criterion and average cell count in the IL and PL were analysed by ANOVA with post hoc t tests. MIA treatment caused a small but signifi cant impairment in ID (p<0.05) as well as more pronounced signifi cant defi cits in reversal learning stages REV1 (p<0.001), REV2 (p<0.001) and REV3 (p<0.001). MIA treatment caused signifi cant increases in the number of PV (p<0.05), CB (p<0.01) and CR positive (p<0.01) GABAergic interneurones in the mPFC. Our data show that MIA treatment induces defi cits in cognitive fl exibility as evidenced by defi cits at the ID stage as well as defi cits in reversal learning. The defi cits observed suggest that MIA treated animals have diffi culty in modifying and adapting their behaviour to new information, rules and situations; indicative of cognitive infl exibility. MIA treatment also caused changes in GABAergic interneurones in the mPFC, suggestive of changes in the excitatory/inhibitory balance of the mPFC vital for aspects of executive function such as working memory. These histological changes may represent part of the underlying neurobiology of the observed defi cits in cognitive fl exibility in these animals and in patients with schizophrenia. Joanne Wallace is the recipient of an MRC CASE studentship award jointly funded funded by the MRC and MSD.

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ALTERED CEREBRAL METABOLISM AND FUNCTIONAL CONNECTIVITY IN A SCHIZOPHRENIA-RELATED DISEASE MODEL: IMPACT OF POLY IC AND THC ON THE DEVELOPING BRAIN Stenson GM, Strathclyde Inst of Pharmacy and Biomedical Sciences, Univ of Strathclyde, 161 Cathedral Street Glasgow G4 0RE g129bs, [email protected] Brett R (1), Dawson N (1),Pratt JA (1) (1) SIPBS, Univ of Strathclude, Glasgow G4 0RE

Increasing evidence suggests a relationship between exposure to environmental risk factors during critical phases of neurodevelopment and subsequent onset of schizophrenia in adulthood (Brown et al. 2000 Am J Psychiatry; 157:438-443, Pope et al. 2003 Drug Alcohol Depend; 69:303–310). Previously, we investigated the interplay between maternal immune activation (MIA) and adolescent exposure to cannabinoids on the precipitation of schizophrenia-related phenotypes. This was tested using a rodent model of MIA by the synthetic analogue of viral double-stranded RNA, polyinosinic:polycytidylic acid (Poly IC) followed by chronic peripubertal exposure to the principal psychoactive constituent of cannabis, Δ9-tetrahydrocannabinol (THC), We found that low-dose intermittent THC treatment throughout the peripubertal period, mimetic of light recreational cannabis abuse, resulted in cognitive infl exibility in adulthood. Furthermore, we demonstrated an environment- environment interaction whereby low-dose intermittent THC treatment to MIA offspring led to enhanced sensitivity to amphetamine compared to phosphate buffered saline-treated (PBS-control) offspring. To elucidate the neural correlates implicated in these observed behavioural perturbances, we investigated the effects of MIA and peripubertal THC treatment on brain imaging signatures and functional connectivity in adulthood. On gestation day 15, pregnant Lister-hooded rats received either a single intravenous injection of Poly IC (4mg/kg) or PBS. Male offspring received either low-dose intermittent THC treatment (3.5mg/kg THC 3 times/week) or vehicle (1% Tween 80 in 0.9% saline) i.p. throughout postnatal days (PD) 35-56 (n=12/group) followed by a 14-day washout period. On PD70, cerebral metabolism was determined using semi quantitative [14C] 2-deoxy-D-glucose (2-DG) autoradiography. We employed the mathematical model, partial least squares regression, to elucidate alterations in functional connectivity networks subserving MIA and THC-induced behavioural perturbances. MIA led to a residual hypermetabolic state within discrete components of the prefrontal cortex (dorsolateral orbital and cingulate cortices-p=0.026, 0.044 respectively) and hypometabolism within the CA3 subfi eld of the hippocampus (p=0.009). The functional connectivity signatures of all these regions indicate a unifi ed MIA effect of aberrant mesocorticolimbic functional coupling in adulthood. Low-dose intermittent THC treatment resulted in an increase in metabolic activity in the dorsolateratal orbital cortex (p=0.013),decreased metabolism within the nucleus accumbens core (0.012) and altered functional coupling between both these regions and neural substrates subserving reward-related learning including prefrontal, septal and amygdala subfi elds. Collectively, these novel cerebral metabolism and functional connectivity fi ndings have facilitated the elucidation of the neural substrates underpinning the behavioural disturbances arising from MIA and peripubertal THC treatment. Furthermore, these data provide new evidence suggesting that different neural systems display distinct sensitivity loads to environmental challenges throughout neurodevelopment. Capacity Award in Integrative Mammalian Biology funded by BBSRC, British Pharmacological Society, Knowledge Transfer Network, MRC and the Scottish Funding Council. A64 ABSTRACTS

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CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITION AND Δ-9-TETRAHYDROCANNABINOL (THC) HAVE INTERACTIVE EFFECTS ON DOPAMINE LEVELS IN THE NUCLEUS ACCUMBENS Stumpenhorst K, Dept of Psychiatry, Oxford Univ, Warneford Hospital Oxford Ox3 7JX [email protected] Käenmäki M(1), Harrison PJ (2), Sharp T (3), Tunbridge EM (2) (1) Univ of Helsinki, Faculty of Pharmacy, P.O. Box 56, Helsinki FIN-00014 (2) Oxford Univ, Dept of Psychiatry, Warneford Hospital, Oxford OX3 7JX (3) Oxford Univ, Dept of Pharmacology, Mansfi eld Road, Oxford OX1 3QT

The frontostriatal dopamine system is a key modulator of cognitive function and psychosis. Dysfunction of this system has been associated with many pathological states, including schizophrenia. Apart from genetic predisposition, environmental factors are also known to infl uence psychosis and cognitive dysfunction. Recent epidemiological and laboratory based studies suggest that Δ-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis, might interact with individual differences in catechol-O-methyltransferase (COMT) activity, an enzyme involved in the breakdown of dopamine, to effect psychosis and cognitive dysfunction (Caspi et al. 2005, Biol Psychiatry 57:1117-1127; O’Tuathaigh et al. 2010, Neuropsychopharmacology 35:2262-2273). In this study we investigated the separate and interactive effects of both acute COMT inhibition and THC administration on extracellular dopamine levels in the dorsal striatum and nucleus accumbens. Microdialysis coupled with high performance liquid chromatography was used to examine the separate and interactive effects of THC (3 mg/kg i.p.) and tolcapone, a brain permeable COMT inhibitor (30 mg/kg i.p.) on dopamine and metabolite levels in awake, behaving mice (C57Bl/6J, male, 7-11 weeks). The main and interactive effects of tolcapone and THC were analysed by repeated-measures ANOVA. Results were considered signifi cant at P<0.05. When administered alone, neither tolcapone nor THC affected extracellular dopamine in either brain area. However, in the nucleus accumbens, but not the dorsal striatum, extracellular dopamine levels signifi cantly increased following THC administration in animals pretreated with tolcapone (p=0.011) but not vehicle. Tolcapone increased 3,4-dihydroxyphenylacetic acid (DOPAC) and decreased homovanillic acid (HVA) in both brain regions (p<0.001) but there was no evidence that this effect was modulated by THC or that THC alone had any effect on DOPAC or HVA. Our data show that THC when co-administered with tolcapone increased dopamine in the nucleus accumbens. Neither tolcapone nor THC infl uenced striatal dopamine when administered alone, consistent with previous data suggesting that COMT does not modulate basal striatal dopamine levels. Our data suggest that interactive effects of COMT and cannabis/THC on dopamine function might underlie the observed interaction between them in precipitating psychosis and cognitive dysfunction. This research was funded by a Wellcome Trust DPhil studentship awarded to KS, a Royal Society Research Fellowship and a Royal Society Project Grant awarded to EMT as well as research grants from Svenska Kulturfonden, Oskar Ölfl und Foundation and University of Helsinki Funds awarded to MK.

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CANNABIS USE AND PSYCHOTIC EXPERIENCES IN UK TEENAGERS - A LONGITUDINAL STUDY USING ALSPAC Gage SH, School of Social and Community Medicine, Univ of Bristol, Canynge Hall, 39 Whatley Road Bristol BS8 2PS [email protected] Hickman M(1), Heron J(1), Munafò MR(2), Zammit S(3) (1) Univ of Bristol, School of Social and Community Medicine, Bristol, UK; (2) Univ of Bristol, Experimental Psychology, Bristol, UK; (3) Univ of Cardiff, Inst of Psychological Medicine and Clinical Neurosciences, Cardiff, UK

Introduction: A consistent association between cannabis use and psychotic experiences (PEs) has been described in previous literature, but confounding by childhood characteristics has been only partially adjusted for in most studies. We aimed to investigate the association with more extensive consideration of potential confounders. Methods: We used the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort (N=3303). Substance use at age 16 was assessed via self-report questionnaire. PEs at age 18 were assessed via semi-structured interviews. Confounders (family history, maternal education, IQ, depression, borderline personality traits, SDQ (strengths and diffi culties), and other illicit drug use) were measured variously by questionnaire and interview. Logistic regression analyses were conducted separately for cannabis use at 16 and PEs at 18, and tobacco use at 16 and PEs at 18, due to collinearity between cannabis use and tobacco use. Results: We observed a strong association between cumulative use of cannabis at 16 and PEs at 18 (unadjusted OR: 1.48, 95%CI: 1.29, 1.71) that was relatively unchanged when adjusting for maternal and childhood confounders (adjusted OR: 1.52, 95%CI: 1.24, 1.85). Associations were greatly attenuated by adjustment for other illicit drug use (fully adjusted OR 1.21, 95%CI: 0.93, 1.58), though independent effects of cannabis and other drugs were diffi cult to determine due to collinearity. Frequency of tobacco use was also associated with PEs. However, this relationship did not attenuate to the same degree when other illicit drug use at baseline was adjusted for (fully adjusted OR 1.31, 95%CI: 1.06, 1.62). A Mentel-Haenszel approach was used to assess the cannabis relationship stratifi ed by tobacco use, showing a small relationship between cannabis use and PEs, controlling for tobacco use (OR 1.21, 95%CI: 1.00, 1.47). There were 85 individuals who smoked cannabis with tobacco even though they rated themselves as non-smokers when asked about tobacco use. Conclusions: We found the predicted relationship between cannabis use and PEs, but adjustment for childhood confounders attenuated the relationship. However, due to collinearity logistic regression analysis is an unsuitable method for investigating this relationship. A more nuanced approach is necessary to tease apart effects from cannabis and tobacco. Although there has been a strong consistent relationship between cannabis and PEs in previous literature, this relationship remains much less clear in relation to long-term effects on psychosis. Future work will utilise novel approaches such as Mendelian Randomisation to investigate causal effects of tobacco on PEs independently of confounding by other drug use. FUNDING: MRC studentship ABSTRACTS A65

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COGNITIVE REMEDIATION TRAINING EFFECTS ARE NOT INFLUENCED BY IQ IN PATIENTS WITH SCHIZOPHRENIA Inamdar A, GlaxoSmithKline, Stockley Park, Uxbridge Middlesex UB11 1BT [email protected] Zucchetto M (1), Gilleen J (2), Maruff P (3), Wexler BE (4), Shabbir S (5), Lund J (6), Shergill S (7), Laruelle M (8), Alexander R(9), Murthy NV (10) (1)Synergy outsourcing, Buckland House, Waterside Drive, Langley Business Park, Slough SL3 6EZ (2)Kings College London, Inst of Psychiatry, De Crespigny Park, London (3) CogState, Level 2, 255 Bourke Street, Melbourne, VIC 3000, Australia (4)Dept of Psychiatry, Connecticut Mental Health Center and Yale Univ, New Haven, Connecticut, USA (5)GlaxoSmithKline, Gunnels Wood Road, Stevenage, UK (6)LEO Pharma, Copenhagen, Denmark (7)Kings College London, Inst of Psychiatry, De Crespigny Park, London (8)Yale Univ, 300 George St., Suite 901, New Haven, CT 06511, USA (9)AstraZeneca, SE-151 85 Sodertalje, Sweden (10)Takeda Global Research & Development, 61 Aldwych, London, UK

Introduction: Multiple novel pharmacological approaches have not been successful in the treatment of Cognitive Impairment Associated with Schizophrenia (CIAS). A potential approach to improve chances of showing benefi t in CIAS could be to combine novel drugs with cognitive remediation training. We recently completed a methodology study to evaluate the effects of Brain Fitness Program (BFP) added to antipsychotic medication [Murthy et al, 2012, Schizophr Res; in press]. While no signifi cant overall benefi cial effects of BFP training on cognitive performance were seen in this study, it is possible that pre-morbid IQ and/or illness-related decline in IQ may infl uence the response to cognitive training [Weickert et al, 2000, Arch Gen Psychiatry; 57:907-913]. Here we present exploratory analyses on the relationship between IQ and BFP training related changes in cognitive performance. Methods: This was an open-label study conducted at six sites; three each in the USA and UK. Fifty-fi ve clinically stable patients [mean (SD) age 31.1(7) years; mean duration of illness 6.4(2.8) years] with schizophrenia (DSM-IV TR) on atypical antipsychotic medication were enrolled. Patients underwent BFP training (1-hour each, up to fi ve times/week) for 8-10 weeks. Pre-morbid IQ was assessed using the NART (National Adult Reading Test) and current IQ by using the WAIS (Wechsler Adult Intelligence Scale -short version). CogState® Schizophrenia Battery (CGSB) was used to measure the effects on cognitive performance before and after completing BFP training. Effect size (ES) (Becker BJ, 1988, Br J Math Stat Psychol; 41, 257–278) and paired t-test were used to evaluate the BFP training effects on cognitive performance. Results: Thirty-seven patients showed normal pre-morbid IQ (≥90) and ≥10-point IQ reduction since illness onset (deteriorated). Nine had normal pre-morbid IQ (≥90) and <10-point IQ reduction (preserved) and the rest had low pre-morbid IQ (86-90) with or without IQ reduction (compromised). In all three IQ based groups, BFP training was associated with small but non-signifi cant effects on CGSB Composite Score [deteriorated group: ES -0.22 , 95% CI -0.527 to 0.085; preserved group: ES -0.49, 95% CI -1.288 to 0.313; and compromised group: ES 0.13, 95% CI -0.228 to 0.493]. Conclusion: Pre-morbid IQ and illness related IQ decline did not signifi cantly differentiate BFP training related effects on cognitive performance in stable patients with schizophrenia.

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A NATURALISTIC EVALUATION OF THE USE OF PALIPERIDONE PALMITATE AT A SOUTH LONDON NHS FOUNDATION TRUST: 6 MONTH INTERIM RESULTS ON THE FIRST 120 PATIENTS Taylor DM, Pharmacy Dept, Maudsley Hospital South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE58AZ [email protected] Attard A - Pharmacy Dept Bethlem Royal Hospital Monks Orchard Rd Beckenham BR33BX

Introduction: Several naturalistic evaluations on new medicines have enabled targeted, effective use of new products and revealed the effects of newly introduced drug formulations on patient outcomes and health economic variables.(Young et al,Acta Psychiatr Scand 2006;114:14-20; Taylor et al,Int J Neuropsychopharmacol 20069:685- 694; Taylor et al,Acta Psychiatr Scand 2007;116:461-466) Paliperidone palmitate (PP) was launched in the UK in April 2011. This is a prospective, non-interventional, observational study of PP in normal clinical practice. Method: All patients prescribed PP are registered and followed-up for 3 years in 3-5 participating NHS trusts. Outcomes include time on treatment, effect on hospital bed stay, effect on healthcare costs, and tolerability. Follow-up will initially be for 6 months (interim analysis reported here) but total 3 years. Change in bed stay and admissions is calculated from bed days in the three years before PP use compared with the three years after. The main effectiveness outcome will be time on treatment. This outcome and change in bed days will be examined in respect to patient and demographic factors. Information on patient outcomes (continuation with treatment, adverse effects, etc) is collected at the time of each injection by pharmacy staff. We have collected data on weight, plasma lipids and plasma prolactin at baseline and then 3 monthly. Baseline data include: age, gender, race, diagnosis, current treatment, prior responsiveness to treatment (as recorded in the medical notes), in-patient status, illness duration, number of previous antipsychotics, reason for prescribing. Results: This reports the baseline patient demographic data on the fi rst 120 patients to be prescribed PP at the South London NHS Foundation Trust. It reports on the time on PP treatment, number of admissions, hospital bed days and associated healthcare costs and tolerability. For the purpose of this interim report the change in bed stay and admissions is calculated for 6 months before PP use compared with 6 months after. Conclusion: To our knowledge this is the fi rst report on the clinical utility of PP in the UK. Funding: This study has been supported by a research fund from Janssen-Cilag.

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NEURAL SUBSTRATES MEDIATING THE COGNITIVE-ENHANCING EFFECTS OF NICOTINE: IMPLICATIONS FOR SELF-MEDICATION IN SCHIZOPHRENIA Mitchelmore RLJ, Inst of Neuroscience, Univ of Newcastle, The Medical School, Newcastle upon Tyne NE2 4HH [email protected] Hasan S (1), Rushforth S (1), Steckler T (2) & Shoaib M (1) (1) Inst of Neuroscience, Newcastle Univ, Newcastle, NE2 4HH. (2) Jannsen Research & Development, Beerse, Belgium.

Cognitive defi cits represent the core defi cits within this disorder: accountable for the majority of disruption to everyday life. Over 80% of patients with schizophrenia smoke compared to just 30% of the general population. This is proposed as a form of self-medication to help combat cognitive problems. A sub-chronic, sub-anaesthetic regimen of NMDA antagonist ketamine was used to induce cognitive defi cits in the odour span task (OST), a non-spatial memory task in which an animal must identify a novel odour from an increasing sequence of odours. 44 hooded-Lister rats trained in the OST and previously exposed to a sub-chronic ketamine regimen (10mg/kg once daily for 5 consecutive days) were implanted with bilateral cannulae. Following recovery animals were habituated to the handling for the local injection procedure and stable task performance was re-established. Nicotine was administered bilaterally at 1, 2 and 4μg along with vehicle treated controls in a crossover design where each animal was tested with each dose, pseudo-randomised over the days. Following a 2 week washout, animals were locally injected with the GABAA agonist muscimol at 0.5μg and 1.0μg dose along with vehicle treatment. Correct stereotaxic placement was confi rmed using Evans blue dye. The experimenter was blinded to treatments throughout all experiments. Local administration of nicotine into the medial prefrontal cortex signifi cantly enhanced performance in ketamine treated animals at all doses tested, the most effective being the 2μg dose (p>0.01). Nicotine was also effective in improving performance in vehicle-treated animals at the 2μg dose (p>0.05). In contrast similar doses of nicotine administered directly into the dorsal hippocampus had no effect. Similarly, local administration of 1μg muscimol signifi cantly impaired performance in control animals only (p>0.05) with no effects observed in groups receiving the same dose into the dorsal hippocampus. The data suggest that the PFC is employed in the execution of the OST task and that nicotine mediates improvement in OST performance via this region. The dorsal hippocampus known to play a role in spatial working memory does not appear to be involved in mediating the cognitive-enhancing effects of nicotine. The results further strengthen the notion that nicotinic acetylcholine receptors may be viable targets for the treatment of cognitive defi cits present within neuropsychiatric disorders. (Research supported by Janssen R&D) A66 ABSTRACTS

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NICOTINE RESTORES THE KETAMINE-INDUCED IMPAIRMENT OF COGNITIVE FLEXIBILITY IN RATS Kohli S, Neuroscience, Newcastle Univ, Framlington Place, Newcastle upon Tyne NE2 4HH [email protected] Shoaib M (1) (1) Inst of Neurosci, Newcastle Univ, Framlington Place, Newcastle upon Tyne NE2 4HH, UK

Impaired cognitive function acts as the most dysfunctional accessory to schizophrenia, and is believed to be induced by altered glutamatergic neurotransmission, particularly within the pre-frontal cortex (PFC). Evidence shows that compared to the 20% of the general population that smoke, this value is around 80% in schizophrenics, and it is postulated that this difference is due to these patients using nicotine for self-medication, in order to improve defi cits in cognition. Sub-chronic ketamine administration was used to model cognitive impairment in the attentional set-shifting task (ASST), which is considered to be dependent on prefrontal cortical activity. In the ASST, the rodent has to form an attentional set towards a particular rewarding stimulus (intra-dimensional (ID) shift), and then shift its attention when the rewarding stimulus is changed (extra- dimensional (ED) shift). 24 male hooded-Lister rats (Harlan UK) were used in total, with 12 being exposed to the ketamine dosing regimen (30mg/kg IP once daily for 5 consecutive days), and 12 to vehicle (saline IP for 5 consecutive days). This was followed by a 2-day washout period prior to the day of the test. An acute nicotine injection (0.1mg/kg IP) was also administered to half the subjects 10-min before the ED-shift of the ASST, where the other 12 received vehicle as a control. Ketamine exposure was found to impair cognitive fl exibility, shown by the reduced ability to shift attention; ketamine treatment correlated with an increased number of trials to reach criterion in the ED-shift compared to control. Performance of the ED shift however, was signifi cantly improved on administration of nicotine, (F (1, 24) = 8.267, p<0.05). In addition, a two-way ANOVA using ketamine-treatment and nicotine administration as factors, revealed a trend towards the interaction of these factors (F (1, 24) = 3.870, p<0.05). The results suggest that nicotine may be effective in restoring the attentional defi cits in cognitive fl exibility induced by sub-chronic ketamine exposure, and that nicotine may be administered by patients with schizophrenia as a form of self-medication, in order to improve their quality of life. Financial Sponsor: Newcastle University

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VARENICLINE ATTENUATES CIGARETTE SMOKING ABSTINENCE-INDUCED DEFICITS IN VISUOSPATIAL WORKING MEMORY IN SCHIZOPHRENIA Wing VC, (1) Schizophrenia Program; (2) Div of Brain and Therapeutics, Dept of Psychiatry (1) Centre for Addiction and Mental Health (CAMH); (2) Univ of Toronto, 33 Russell St. BACDRL, Room 1910A Toronto, ON Canada M5S 2S1 [email protected] Wass CE (1,2), George TP (1,2) (1) Schizophrenia Program, Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada. (2) Division of Brain and Therapeutics, Dept of Psychiatry, Univ of Toronto, Toronto, ON, Canada.

Background: People with schizophrenia have pervasive cognitive defi cits related to prefrontal cortical dopamine (DA) dysfunction (e.g. visuospatial working memory; VSWM), and cigarette smoking abstinence worsens such cognitive performance in schizophrenia. The presence of cognitive defi cits in domains such as VSWM may predict smoking cessation failure in schizophrenia, and therefore could be an important target for the development of smoking cessation therapies in this population. Aims: To evaluate the effect of the nicotinic partial agonist and smoking cessation medication varenicline tartrate (Champix®) on cognitive function in smokers with schizophrenia, in comparison to healthy control smokers, under smoking satiation, overnight abstinence and smoking reinstatement conditions. Methods: A 3-day laboratory paradigm incorporating baseline smoking, overnight abstinence and smoking reinstatement conditions, was employed (Sacco, KA et al., (2005) Arch Gen Psych 62: 649-59). Across the three separate test weeks, schizophrenia (n=10) and non-psychiatric control (n=10) smokers were pre-treated (using a counterbalanced sequence across subjects) with varenicline (0, 0.5 and 1mg BID) during the 3 test days and assessed on the VSWM task (Hershey et al., (1998). Neuropsychology, 12: 52-64) under each smoking condition. Results: Overnight smoking abstinence induced a defi cit in VSWM at the 30-second delay condition, in smokers with schizophrenia (main effect of Session p=0.05; abstinence vs. reinstatement p=0.02), but not in control smokers. Varenicline altered VSWM compared to placebo in smokers with schizophrenia (Session x Dose interaction: p=0.02) but not control smokers. Following varenicline pre-treatment (0.5 or 1mg, BID), abstinence did not impair and (p=0.01) and reinstatement did not improve (p=0.007) VSWM in schizophrenia smokers. Compared to placebo, the highest varenicline dose (2mg/day) impaired VSWM in smokers with schizophrenia under baseline smoking but not abstinence or reinstatement conditions (p=0.02). Discussion: We have replicated our previous fi nding that abstinence from cigarette smoking induces defi cits in VSWM at the 30-second delay condition, despite differences in the VSWM task employed across studies. Moreover, the observation that sub-chronic varenicline (i.e., three doses) attenuated abstinence-induced cognitive defi cits in persons with schizophrenia (versus controls) suggest that it is capable of counteracting changes in VSWM during cigarette smoking abstinence and reinstatement. This has important implications for the development of nicotinic partial agonists as cognitive enhancers and tobacco dependence pharmacotherapies in people with schizophrenia. Financial Support: This work was funded in part by Ontario Mental Health Foundation (OMHF) and Canadian Institutes of Health Research (CIHR; MOP#115145) Operating Grants, the Canada Foundation for Innovation Leader Opportunity Fund (CFI-LOF #19229), and the University of Toronto Chair in Addiction Psychiatry to TPG. VCW and CEW were supported by Postdoctoral Research Fellowships from the Centre of Addiction and Mental Health (CAMH).

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NICOTINE IS ASSOCIATED WITH IMPROVED COGNITIVE PERFORMANCE BUT WORSE METABOLIC PROFILE: PRELIMINARY FINDINGS FROM A COHORT OF FIRST EPISODE PSYCHOSIS PATIENTS Russo M, Psychosis Studies, Inst of Psychiatry, 16 De Crespigny Park London SE5 8AF [email protected] Falcone MA (1), O’Connor J (1), Wiffen B (1), Sood P (1), Hockey L (1), Omer S (1), Liu M (1), Ismail K (1), Atakan Z (1), Smith S (1), Theleritis C (1), Murray R (1), Reichenberg A (1), Bonaccorso S (1) (1) Dept. of Psychosis Studies-Inst of Psychiatry, King’s College, London.

BACKGROUND Psychotic patients have higher smoking prevalence rates compared to healthy population (Winterer et al., 2010 Curr Opin Psychiatry; 23:112–9). It has been found that alpha-7 nicotinic receptor agonists improve cognitive functions in rhesus monkeys (Castner et al, 2011 Biol Psychiatry 69:12 – 18) and are involved in the reduction of activity of the default network in patients with schizophrenia (Tregellas et al. 2011, Biol Psychiatry 69:7 -11). Nicotine dependence, however, exposes smokers with co-occurring psychotic disorders to increased risk of smoking related morbidity and mortality (Bobes et al., 2010, Schizophr Res; 119:101-9). In this study, we sought to investigate the correlates of smoking in neuropsychological performance and metabolic parameters in a sample of fi rst episode psychosis (FEP) patients. METHOD Sixty-six FEP patients underwent a neuropsychological battery assessing premorbid IQ, current IQ, attention, processing speed, executive functions, visual and verbal memory, working memory and verbal fl uency. Metabolic and anthropometric parameters (BMI, fasting blood glucose, waist, waist-hip ratio, cholesterol, triglyceride, HBA1C etc.) were also estimated. A multivariate analysis of variance, co-varying for ethnicity, was used to investigate the relationship between smoking status and both cognitive and metabolic measures. RESULTS The sample was composed of 43 males and 23 females, 27 black people, 28 white people, and 11 of other ethnicities. Eighteen were non-smokers and 48 were current smokers. Mean age was 31.6 (SD=±11.4) for non-smokers, 28.3(SD=±7.3) for smokers. No difference in severity of symptoms on PANSS, pre-morbid IQ and in chlorpromazine equivalents emerged. A signifi cant difference between smokers and no-smokers was noted for ethnicity (chi-square =.004). Smokers showed a better performance (mean time in sec=41.7, SD=± 15.1) on attention (Trail Making Test – Part A) compared to non- smokers (mean time in sec= 54.54, SD= ± 33.6) (p=0.05). Smokers (mean=62.2, SD= ± 26.03) also showed a trend (p=0.08) towards a better performance compared to non-smokers (mean= 46.7, SD= ± 21.4) on visual memory at the visual reproduction test (Wechsler Memory Scale-III). For metabolic parameters, current smokers showed an increased cardio-vascular risk (p=.048) with lower level of HDL (mean=1.3, SD=±0.3) compared with non-smokers (mean=1.6, SD=±0.5). CONCLUSIONS This investigation shows an association between smoking status and cognitive function, namely attentive processes, and metabolic profi le. We cannot assume the relationship with cognitive functions is causal but further investigations are necessary to understand the relationship between nicotine receptor agonists and cognition with potential implications for developing drugs to treat cognitive impairment in schizophrenia and other psychoses. Acknowledgement: Authors wish to acknowledge the NARSAD - Young Investigator Award 2009 to Stefania Bonaccorso – as source of fi nancial sponsorship. ABSTRACTS A67

TG01

EFFECTS OF THE MU OPIOID RECEPTOR ANTAGONIST GSK1521498 ON HEDONIC AND CONSUMMATORY BEHAVIOUR: A PROOF OF MECHANISM STUDY IN BINGE EATING OBESE SUBJECTS Ziauddeen H, Psychiatry, Univ of Cambridge, Box 289, Level 4, IMS Addenbrooke’s Hospital, Cambridge CB2 0QQ [email protected] Chamberlain SR(1,2,6), Nathan PJ(1,2), Koch A(1) , Napolitano A (1), Bush M(1), Tao WX(3), Maltby K(1), Skeggs AL(1), Brooke AC(1), Cheke LG(7), Clayton NS(7), Farooqi IS(5), O’Rahilly S(5), Richards DB(1, 4), Fletcher PC(2, 6), Bullmore ET(1, 2, 6) (1) Medicines Discovery and Development, GlaxoSmithKline (GSK), Clinical Unit Cambridge, Addenbrooke’s Centre for Clinical Investigations (ACCI), Cambridge, UK (2) Dept of Psychiatry, Behavioural & Clinical Neuroscience Institute, Univ of Cambridge, UK (3) Discovery Biometrics, GSK, USA (4) Academic Discovery Performance Unit, GSK ACCI,,Cambridge, UK (5) Inst of Metabolic Science, Univ of Cambridge, UK (6) Cambridgeshire and Peterborough Foundation Trust, Cambridge, UK (7) Dept of Experimental Psychology, Univ of Cambridge, UK

Introduction: The mu-opioid neurochemical system is a key mediator in the hedonic and motivational processing of food rewards. Dysregulation of the system has been implicated in the pathophysiology of binge-eating, a behaviour that is strongly linked to obesity. The aim of this study was to evaluate the effects of four weeks of treatment with GSK1521498, a novel mu selective opioid antagonist, on hedonic and consummatory aspects of eating behaviour, and on weight, in obese subjects with high binge-eating scores. Method: Adults with body mass index ≥30 kg/m2 and binge-eating scores ≥ 19 received one-week single-blind placebo run-in, and were then randomized to 28 days with either 2mg/day GSK1521498, 5mg/day GSK1521498, or placebo (N=21 subjects per arm) in a double-blind parallel group design. The outcome measures were body weight, fat mass, hedonic and consummatory eating behaviour during inpatient food challenges, safety, and pharmacokinetics. The primary analysis for outcome measures was the comparison of change scores in the higher dose treatment group versus placebo, using analysis of covariance (ANCOVA), at each relevant time point. Results: GSK1521498 (2mg and 5mg) was not different from placebo in its effects on weight, fat mass, and binge eating scores. However, compared with placebo, 5mg/day GSK1521498 caused a signifi cant dampening of overall hedonic responses to sweetened dairy products (p=0.0115) with predominant effects on high fat (p=0.0157) and high sugar samples (p=0.0024). Compared with placebo, 5mg/day GSK1521498 also reduced total calorifi c intake during ad libitum buffet meals (p=0.0087), particularly the intake of high fat desserts (p=0.023). These fi ndings were dose-dependent, with 2mg/day GSK1521498 not differentiating from placebo on these measures, and with evidence for signifi cant correlational relationships with between-subject variation in trough plasma concentrations of GSK1521498. GSK1521498 was generally well tolerated and no new safety signals were identifi ed. Conclusion: Antagonism of mu-opioid receptors with the higher dose of GSK1521498 (5mg/day) had a signifi cant impact on hedonic experience of food as well as food intake, and was well tolerated. The potential for these fi ndings to translate into clinically signifi cant effects in the context of binge-eating and weight regain prevention is under consideration. Financial sponsorship: This study was funded and conducted by GSK. HZ is a Clinical PhD Fellow on the Wellcome Trust and GSK funded Translational Medicine & Therapeutics (TMAT) program. The following authors are GSK employees and have shares in the company: AK, WT, KM, AN, AS, AB, DR, MB, EB, PN.

TG02

EFFECT OF META-CHLOROPHENYLPIPERAZINE (MCPP) ON EMOTIONAL PROCESSING AND MOOD IN HEALTHY VOLUNTEERS Thomas JM, School of Psychology, Univ of Birmingham, Frankland Building, Edgbaston, Birmingham B15 2TT [email protected] Tomlinson J (2), Hassan-Smith Z (2), Dourish CT (3), Higgs S (1) (1) Univ of Birmingham, Birmingham, B15 2TT; (2) Univ of Birmingham, Birmingham, B15 2TH; (3) P1vital, Univ of Oxford, Oxford OX3 7JX

The 5-HT2C receptor agonist meta-chlorophenylpiperazine (mCPP) has been reported to decrease food intake and increase psychological and physiological symptoms of anxiety in healthy volunteers. However, the specifi c emotional processes that mediate the anxiety response are unclear. In the present study, we used the P1vital® Oxford Emotional Test Battery (ETB) and questionnaires to investigate the effects of mCPP on emotional processing and mood, using a between-subjects double blind placebo controlled design. 24 male and 24 female participants were randomly assigned to placebo, 15mg or 30mg mCPP treatment groups (8 males and 8 females per group). Participants completed a battery of questionnaires (BDI/STAI/PANAS - pre and post drug) and appetite and mood ratings throughout the day, and were tested using the ETB post drug only. There was no signifi cant effect of condition on the questionnaires used. However, 30mg mCPP signifi cantly reduced appetite ratings and increased physical symptoms, including nausea, in both male and female participants. Results from the ETB showed that during a surprise free recall task (of previously presented emotional words) participants were able to correctly recall a higher number of words after 15mg and 30mg mCPP compared to placebo. When shown previously presented emotional words (valid), and unseen distracter words (invalid) in an emotional recognition memory task, participants given 30mg mCPP exhibited higher target sensitivity to valid words compared to placebo. In this task, female participants given 30mg mCPP were also more accurate at recognising previously presented positive emotional words. Female participants given 15mg mCPP also responded faster and less accurately on a dot probe task, when the mask was a fearful facial expression. The enhancement of accuracy, recall, and target sensitivity in the ETB tasks by mCPP, independent of valence, suggests the drug may have an effect on memory; whereas the more specifi c effect of enhanced speed and lower accuracy to fear stimuli, suggests an effect on mood - particularly in female participants. Jason Thomas is supported by the Steve Cooper Ph.D. CASE studentship funded by the BBSRC and P1vital.

TG03

DISRUPTIVE EFFECTS OF BUPROPION ON FEEDING BEHAVIOUR AND THE BEHAVIOURAL SATIETY SEQUENCE IN RATS Rodgers RJ, Behavioural Neuroscience Lab, Inst of Psychological Sciences, Univ of Leeds, Woodhouse Lane, Leeds LS2 9JT [email protected] Wright F (1) (1) Behavioural Neuroscience Lab Inst of Psychological Sciences Univ of Leeds Leeds LS2 (JT

Bupropion is a dopamine and noradrenaline reuptake inhibitor (Ascher et al. 1995 J Clin Psychiatry 56: 395-401) that also acts as a non-competitive nicotinic receptor antagonist (Slemmer et al. 2000 JPET 295: 321-327). Although best known as an atypical antidepressant and aid to smoking cessation, bupropion has also been reported to reduce food intake and weight gain, both when given alone (e.g. Zarrindast & Hosseini-Nia 1988 Gen Pharmacol 19: 210-204) and in combination with other agents (e.g. Greenway et al. 2009 Obesity 17: 30-30). However, little is currently known about the behavioural specifi city of such effects. This is a signifi cant gap in our knowledge base, especially as the compound has been widely reported to have psychostimulant-like properties (e.g.Soroko et al. 1977; Cooper et al. 1980 JPET 215: 127-134; Zarrindast et al. 1996 Eur Neuropsychopharmacology 6: 299-303; Redolat et al. 2005 Psychopharmacology 177: 418-427). In the present study, we have evaluated the behavioural effects of acute bupropion HCl (Tocris Bioscience; 10-40 mg/kg, i.p.) in habituated, non-deprived adult male hooded Lister rats tested for one hour with palatable mash. A within-subjects design (Latin Square; inter-test interval = 3days) was employed, and test sessions were recorded on DVD. Behaviour was scored by a highly trained observer (intra-rater reliability > 0.8) using ethological analysis software (Hindsight v1.4; Weiss 1995). Measures comprised one-hour mash intake and latency to feed, as well as the frequency and duration of feeding, drinking, grooming, scratching, resting, locomotion, rearing and sniffi ng. Behavioural data were analysed both as session totals and by timebin (12 x 5min). ANOVA confi rmed that bupropion reduced food intake (F3,27 = 7.04, p = 0.001) and time spent feeding (F3,27 = 12.41, p < 0.001), effects that were statistically signifi cant at the highest dose only. However, our analyses also revealed that the same dose (40 mg/kg), but not lower doses, signifi cantly increased the frequency of feeding and rearing (F3,27 > 11.59, p < 0.001) as well as the frequency and duration of sniffi ng and locomotion (F3,27 > 11.72, p < 0.001). Timecourse analyses confi rmed that the behavioural activating effects of 40 mg/kg bupropion were evident throughout the entire test session, thereby completely disrupting the structural integrity of the normal behavioural satiety sequence (BSS). As such effects were not seen at non-anorectic dose levels, we conclude that the appetite suppressant effects of acute bupropion are behaviourally non-specifi c and arise largely if not entirely from its psychostimulant-like properties. A68 ABSTRACTS

TH01

THE ROLE OF THE NMDA RECEPTOR AND B-ADRENORECEPTOR IN REWARD MEMORY RECONSOLIDATION: A META-ANALYSIS Das RK, Clinical Psychopharmacology Unit, UCL, 1-19 Torrington Place London WC1E 7HB [email protected] Freeman TP (1), Kamboj S(1) Clinical Psychopharmacology Unit, 1-19 Torrington Place London, WC1E 7HB

Introduction: There is growing interest in the manipulation of memory reconsolidation mechanisms for their potential in treating drug addiction. However, there is currently no quantitative information examining the overall effect of reconsolidation blockade in attenuating reward memory and no systematic analysis of the moderators of intervention effects. In order to inform effective translation of fi ndings from rodent studies to human populations, it is necessary to understand these variables and design experiments accordingly. As the most promising and best-studied targets for pharmacological reconsolidation blockade are the B-adrenergic and NMDA receptors, the current study conducted a meta-analysis of the effects of antagonism of these receptors in reward memory reconsolidation. Method: ISI web of knowledge, PubMed, PsychInfo and SIGLE online databases were searched for studies examining reconsolidation in a reward conditioning paradigm using either an NMDA or B-adrenergic antagonist. Key journals were hand-searched and authors contacted for unpublished information. The search retrieved 32 studies, constituting 56 independent samples for which effect sizes, information on test drug, dose, administration timing, administration route and conditioning and reactivation procedure were extracted. One study (4 samples) was removed due to outlying status. A random-effects model was used to perform the analysis. Results: NMDA antagonism was associated with a large, robust effect on reward memory reconsolidation [.613 (95% CI = .522(lower) to .69 (upper)]. The effect of B-AR antagtonism was much smaller [0.24 (95% CI = -0.156(lower) to 0.321 (upper)], with limited reliability. Moderator analysis revealed that drug administration timing and primary reinforcer, but not learning paradigm, signifi cantly moderated effect sizes. Discussion: The analysis suggests that the NMDAR might provide a better target for interfering with reward memory reconsolidation than the B-AR. Furthermore, sensitivity of reward learning to disruption may vary based on reinforcer (e.g ethanol vs. cocaine) and methodological factors. Translational attempts at using reconsolidation blockade to treat human addicts must therefore take these factors into account. It may be that some addictions are more amenable to reconsolidation treatment than others. This work was funded by the ESRC

TH02

ASSOCIATIVE BLOCKING TO REWARD-PREDICTING CUES IS ATTENUATED IN KETAMINE USERS BUT CAN BE MODULATED BY IMAGES ASSOCIATED WITH DRUG USE Freeman TP, Clinical Psychopharmacology Unit, Univ College London, 1-19 Torrington Place, London WC1E 7HB [email protected] Morgan CJA(1) Pepper F(1) Howes OD(2,3) Stone JM(2,3) Curran HV(1) (1) Clinical Psychopharmacology Unit, Univ College London, London, UK (2) Div of Experimental Medicine/ MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, London, UK (3) Inst of Psychiatry, King’s College London, Camberwell, UK

Blocking is a selective learning process that is attenuated in schizophrenia, can be modulated by cue salience, and is accompanied by changes in selective attention. Repeated exposure to ketamine can model aspects of schizophrenia, and users show attentional bias towards images of the drug. This study aimed to establish whether (i) ketamine users show a reduction in blocking to reward-predicting cues and (ii) this effect can be modulated by images associated with drug use. We also investigated drug cue induced overshadowing, an effect recently found in abstaining smokers (Freeman TP, et al. 2012, Psychological Medicine 42: 161-171). Ketamine users (n=18) and polydrug controls (n=16) were assessed on the Drug Cue Reward Prediction Error Task (DCRPET; [2]) which assesses the effects of neutral and drug related cues on reward-based associative learning processes. Following Pavlovian conditioning between cues and outcomes, accuracy and importance ratings to individual cues were used to index blocking and overshadowing. Delusions, schizotypy, depression and ketamine dependence were also measured. The ketamine using group has used ketamine for 10.39 (±3.58) years, currently taking 9.27 (±8.40) grams over 4.67 (±1.88) days per week, had moderate to high dependence, and elevated delusional, schizotypal and depressive symptoms compared to controls. Ketamine users showed a reduction in blocking as evidenced by higher accuracy to blocked cues than controls (t32 = 2.308, p = 0.032). Drug-related cues were most resistant to blocking in this group, with ketamine users scoring higher than controls on accuracy (t32 = 2.563, p = 0.015) and importance ratings (t32 = 3.296, p = 0.002) to these cues. Both groups showed overshadowing of neutral cues by drug cues (F1,32 =4.541, p = 0.041), and ketamine users gave both overshadowing cues higher importance ratings than controls (F1,32 =6.161, p = 0.018). These fi ndings are the fi rst to link glutamatergic disruption with a reduction in blocking. Drug cues were the most resistant to blocking and were also rated as more important for earning money in ketamine users, suggesting that blocking may contribute to aspects of addictive behaviour as well as schizophrenia. In particular, these fi ndings highlight the importance of competition between drug-related and other ‘alternative’ rewards in addiction (Goldstein RZ, Volkow ND 2011, Nature Reviews Neuroscience 12 652-669) and raise concerns about the effi cacy of reward- based contingency management treatment in high risk, drug associated contexts. This study was funded by an MRC/ESRC interdisciplinary studentship to TP Freeman.

TH03

THE EFFECT OF LONG-TERM KETAMINE USE ON COGNITION AND PSYCHOPATHOLOGY Pepper FS, Psychosis Studies, Inst of Psychiatry, Denmark Hill, London SE5 8AF fi [email protected] Stone JM (2), Howes OD (1,2), Morgan CJA (3) (1) Psychosis Studies, Inst of Psychiatry, KCL, Denmark Hill SE5 8AF (2) Div of Experimental Medicine/ MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, London W12 0NN (3) Clinical Psychopharmacology Unit, UCL, Gower Street, London WC1E 6BT

Background: Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to induce schizophrenia-like symptoms. A one-off dose can induce psychedelic effects (Krystal et al., 1994) and produce schizophrenic-like symptoms and memory impairments. Preclinical research into the chronic effects of ketamine, have found that it produces “schizophrenic-like” changes in rat brains (Keilhoff et al., 2004, Biological Psychiatry, 56(5), 317-322) and working memory impairments (Tan et al., 2011, Plos One, 6(6), 1-8). The present study aimed to test whether frequent, chronic ketamine use would be associated with psychotic-like symptoms and impaired neurocognitive function. Methods: An independent groups design compared eighteen frequent ketamine users (using the drug more than four times a week) and fi fteen control subjects, matched with the ketamine users for gender and IQ. Participants completed an adapted Comprehensive Assessment of At-Risk Mental State (CAARMS) that only identifi ed positive symptoms, emotional disturbance and negative symptoms. In addition, volunteers partook in tests of psychopathology and cognitive function. Results: Ketamine users showed a pattern of psychopathology and cognitive impairment consistent with previous studies. In the CAARMS questionnaire, ketamine users scored signifi cantly higher for severity (U = 13.000 (N1 = 17, N2 = 15), p < 0.05) and frequency (U = 13.000 (N1 = 17, N2 = 15), p < 0.05) of positive symptoms than non ketamine-taking polydrug controls. There was also a trend for a group difference in the severity of negative symptoms (U = 72 (N1 = 16, N2 = 15), p = 0.060). Conclusions: Acute models of ketamine have been shown to induce positive symptoms similar to those seen in schizophrenia (Newcomer et al., 1999). The fi ndings of the current study were that frequent, long-term ketamine users show greater levels of “positive” symptoms than controls, although lower levels than observed in ‘prodromal’ individuals in addition to emotional disturbances. These may be the consequence of prolonged NMDA-receptor blockade, or pre-existing differences between ketamine users and controls. Sources of Financial Sponsorship: The MRC provided funding ABSTRACTS A69

TH04

EXTRACTS OF KHAT (CATHA EDULIS) INCREASE DOPAMINE RELEASE AND BIND TO D1 AND D2 DOPAMINE RECEPTORS IN RAT STRIATUM Ismail M, Inst of Pharmaceutical Science, King’s College London, c/o Prof Peter Hylands, School of Biomedical Sciences Franklin-Wilkins Bldg 150 Stamford Street London SE1 9NH [email protected] Houghton P (1), Rose S (2) (1) Inst of Pharmaceutical Sciences, School of Biomedical Sciences, Franklin-Wilkins Building, 150 Stamford Street London SE1 9NH (2) HB2 46W, Hodgkin Building, Inst of Pharmaceutical Sciences, School of Biomedical Sciences, Guy’s Campus, London SE1 1UL

The psychostimulant effect of Khat (Catha edulis) has been attributed to cathinone via alteration of brain dopaminergic function; however, other components of the plant may also contribute to this effect. We investigated the chemical components of Khat, and the effect of extracts of Khat on dopamine release and dopamine receptor binding in order to determine the role of the non-cathinone extracts of constituent cathedulin alkaloids on the stimulant effects of Khat. Mira and Herari Khat were macerated in H2O or MeOH (1:4 w:v.) for 3h at room temperature and then fi ltered. The water extract was freeze dried whereas the methanolic extract was concentrated < 10mL using a rotary evaporator and the remaining water was removed by freeze drying. Fresh aqueous extracts were made as above but without freeze-drying. The composition of the extracts was determined by LC/MS. The effect of the methanolic and aqueous extracts of Khat, (-)cathinone and (-)norephedrine were determined on 3H-DA release from rat striatal slices and D1 and D2 receptor binding in rat striatal membrane fractions. High levels of (-)-cathinone were found in the fresh extracts of both Herari and Mira Khat (2.9-4.7ug/mg extract). The number of cathedulin alkaloids varied between the individual extracts although quantifi cation of the K11 and K19 cathedulins were similar between extracts. The concentration of (-)-cathinone was lower in the aqueous extract than in the methanolic extract. The constituent alkaloids, (-)cathinone and (-)norephedrine, as well as the cathedulin alkaloid fractions all induced 3H-DA release from striatal tissue slices in vitro. The freeze dried aqueous extracts were 25% less potency than fresh aqueous extracts. Mira was more potent than Herari. The cathedulin alkaloids extract fractions also induced 3H-DA release. Both the aqueous and methanolic extracts of Mira and Herari Khat displaced 3H- SCH23390 and 3H- spiperone from D1 and D2 receptors respectively. Only cathinone displaced 3H- SCH23390 from D1 receptor. By contrast, the cathedulins, with much larger molecules [MW = 600-2000Da], and with esterifi ed dihydroagarofuran-based core, showed no binding to either D2 or D1 receptors. Therefore it is likely that the cathamines and not the cathedulins contribute to the displacement of D1 and D2 receptor binding but further work is required to determine the receptor binding properties of cathinone. In conclusion these data show that the aqueous and methanolic extract of Khat contained (-)cathinone, (-)norephedine and a number of cathedulin alkaloids, and all these contribute to the psychotropic effects of Khat. *I have no source fi nancial sponsorship at present. The study I am presenting is my previous research which was partly sponsored by King’s College London.

TH05

INTRAVENOUSLY ADMINISTERED PSILOCYBIN IN THE FMRI ENVIRONMENT - A PHENOMENOLOGICAL ANALYSIS Turton S, The Medical School, Univ of Sheffi eld, Beech Hill Road, Sheffi eld S10 2RX mdc06st@sheffi eld.ac.uk Carhart-Harris RL (1), Feilding A (2), and Nutt DJ (1) (1) Neuropsychopharmacology Unit, Imperial College London, Burlington Danes Bldg, Hammersmith Hospital Campus, 160 Du Cane Rd, London W12 0NN; (2) The Beckley Foundation, Beckley Park, Oxford, OX3 9SY

Introduction: This study aimed to investigate the phenomenology of the perceptual changes caused by the psychedelic agent psilocybin (found in ‘magic mushrooms’) when administered intravenously in a magnetic resonance imaging (MRI) scanner. The subjective effects of psilocybin have been previously documented (Pahnke, 1969, Int Psychiatry Clin 5(4):149-62, Studerus et al, 2011, J Psychopharmacol 25(11):1434-52) however, this provides an opportunity to investigate the effects when psilocybin is administered in a novel manner (intravenous injection) and setting (MRI scanner). Methods: Fifteen healthy volunteers enrolled in a study investigating the brain effects of intravenous psilocybin using functional MRI (fMRI) imaging (Carhart-Harris et al. 2012, Proc Natl Acad Sci, 109(6):2138-2143). The study consisted of one placebo scan and a second scan during which 2mg of psilocybin were administered intravenously. Following the second fMRI scan participants underwent a semi-structured interview, allowing them to describe and elaborate on their experience. These interviews were fi lmed and the content analysed using an interpretative phenomenological analysis methodology. Results: The peak effects of psilocybin lasted between 15-30 minutes. The two phenomenological categories that arose from the analysis consisted of experiences related to the fMRI scanner and the research environment, and experiences related to the perceptual changes caused by the psilocybin. Key components relating to the scanner environment were: the scanner having a negative effect on the experience (n=11), the research environment having a negative effect on the experience (n=11) diffi culty with the scanner noise (n=10), sense of sensory deprivation (n=8) and preferring a more ‘natural’ environment (n=9). Components relating to the perceptual changes included visual hallucinations or distortions (n=15), physical sensations (n=12), auditory distortions (n=7), altered time perception (n=13), altered cognition (n=13), positive mood effect (n=12) and altered sense of self (n=10). Furthermore there were some additional effects associated with more intense drug effects, such as sensations of melting or merging (n=4) or sense of an external presence (n=6). Discussion: This study identifi ed a number of unique phenomena associated with the psilocybin experience in the MRI scanner environment. Additionally there are phenomena consistent with those previously published (Hasler et al. 2004, Psychopharmacology 172:145–156) suggesting congruence between many aspects of the experience of intravenous psilocybin within an MRI scanner with that of oral psilocybin in other environments. Hopefully these results will stimulate further research into the phenomenology of the subjective effects of psilocybin. This study was supported by grants from the University of Sheffi eld and the Wellcome Trust.

TH06

EFFECT OF REPEATED MEPHEDRONE ON CORE BODY TEMPERATURE AND LOCOMOTOR ACTIVITY IN THE RAT Shortall SE, School of Biomedical Sciences, Univ of Nottingham, Medical School, Queens’ Medical Centre, Nottingham NG7 2UH [email protected] Green AR (1), King MV (1), Fone KCF (1) (1) School of Biomedical Sciences, Univ of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, NG7 2UH

The effects of the illicit cathinone derivative, 4-methylmethcathinone (mephedrone) are commonly compared by human users to 3,4-methylenedioxymethamphetamine (MDMA). MDMA can cause fatal hyperthermia in users, but has varying effects on body temperature in rodents depending on housing conditions. Our previous studies showed that both acute mephedrone and MDMA caused hypothermia in singly housed rats, although this effect was transient for mephedrone (King et al., 2011, J Psychopharmacol 25: A40). Since users of mephedrone tend to re-dose during a single session (Carhart-Harris et al., 2011, Drug Alcohol Depen 118, 19-22), this study investigated the effects in rats of repeated mephedrone administration on body temperature and activity using radiotelemetry. Individually housed young-adult male Lister hooded rats (n=5 per group, 323-353 g on day of testing, CRUK) were surgically implanted under isofl urane anaesthesia with a telemetry transmitter in the peritoneal cavity (day 0) and allowed to recover for 10 days. On day 10, rats received a total of three injections of mephedrone HCl (10mg/kg i.p., Ascent scientifi c) or saline vehicle (1 ml/kg), once every two hours over 4 hours (to mimic binge dosing in humans). Temperature and activity were automatically recorded in the home cage for 10 s every 2 min for the duration of the experiment (6 h). Frontal cortex, hippocampus, striatum and hypothalamus were collected 7 days after dosing for quantifi cation of monoamine neurotransmitters and their major metabolites using high performance liquid chromatography with electrochemical detection (HPLC-ED). Mephedrone caused a brief (40 min) decrease in core body temperature after the fi rst and second injection compared to vehicle (p<0.01, repeated measure ANOVA with Bonferroni post-hoc). In addition, there was a signifi cant increase in locomotor activity following all three injections of mephedrone (p<0.05, repeated measures ANOVA, Bonferroni post-hoc). There was no signifi cant difference in temperature or activity between each injection (p>0.05, repeated measures ANOVA). Mephedrone had no effect on the concentration of the monoamines or their metabolites in any brain region one week post-injection. Mephedrone caused transient hypothermia and hyperactivity which was unaffected by repeated dosing. Both activity and temperature returned to vehicle control levels before administration of the second and third injections suggesting that mephedrone has a short duration of action and that the repeated dosing schedule used did not cause sensitisation. There was also no evidence to suggest that mephedrone was neurotoxic using this dosing schedule. This study was funded by the University of Nottingham, School of Biomedical Sciences. A70 ABSTRACTS

TH07

THE ROLE OF THE 5-HT1 AND 5-HT2 RECEPTOR IN MDMA-INDUCED EFFECTS ON MEMORY AND MOOD van Wel JHP, Neuropsychology & Psychopharmacology, Maastricht Univ, Universiteitssingel 40 6229ER Maastricht [email protected] Kuypers KPC(1), Theunissen EL(1), Bosker WM(1), Bakker K(1), Ramaekers JG(1) (1) Maastricht Univ, Universiteitssingel 40, 6229ER Maastricht

Introduction: Single doses of MDMA or “ecstasy” have been shown to cause impairment of memory, improvement of impulse control and positive mood. The neuropharmacological mechanisms underlying these effects are to date not clear. This study aimed to investigate the role of the 5-HT2A and the 5-HT1A receptors in MDMA-induced memory impairment, improved impulse control and positive mood. It was hypothesized that pretreatment with ketanserin, a 5-HT2A receptor blocker, and pindolol, a 5-HT1A receptor blocker, would negate the MDMA-induced effects on memory, impulse control and mood. Methods: Subjects (N=17) participated in a double-blind, placebo controlled, within-subject design involving 6 experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 minutes. T1-T2 combinations were: placebo-placebo, 20mg pindolol -placebo, 50mg ketanserin - placebo, placebo - 75mg MDMA, 20mg pindolol - 75mg MDMA and 50mg ketanserin - 75mg MDMA. Memory function and impulse control were assessed at Tmax of MDMA by means of a word learning task, a spatial memory task, a prospective memory task, a cue-dependent reversal learning task a stop-signal task (SST) and a matching familiar fi gures task (MFF20). To assess mood, subjects completed the Profi le of Mood States (POMS) questionnaire. Results: MDMA signifi cantly impaired memory performance (WLT30 immediate recall p<.01, spatial memory localization error p<.01) and impulsivity measures (SST stop-reaction time p=.010, MFF20 reaction time p<.000). MDMA also increased positive (vigor, arousal, friendliness, elation, positive mood) and negative affect (anxiety, confusion) as assessed by the POMS questionnaire. Pretreatment with a 5-HT2A receptor blocker prevented MDMA-induced impairment in the word learning task and blocked MDMA effects on positive affect, but not negative affect. Blockade of the 5-HT2A receptor did not affect performance on the spatial and prospective memory task or any of the impulsivity tasks. Pretreatment with a 5-HT1A blocker did not affect the effects of MDMA on any of the measures. Conclusions: 5-HT2 receptors mediate verbal memory impairment and positive moods induced by MDMA. The 5-HT1 receptors do not appear to be involved in MDMA effects on memory, mood or impulse control. This research was funded by the Netherlands Organisation for Scientifi c Research (NWO), grant number: 400-05-096, awarded to JR.

TH08

CO-OPERATION IS POSITIVELY INFLUENCED BY ACUTE MDMA Ferguson B, Clinical Psychopharmacology Unit, Univ College London, 1-19 Torrington Place, London WC1E 6BT [email protected] Stewart L, Fenton R, Jones L, Swaboda N, Roberts RE, Morgan CJA, Curran HV

Co-operation between two parties and trust are seen as crucial to successful psychotherapy (Lambert, M. J., & Barley, D. E., 2002, Psychotherapy, 38, 357-361). Higher levels of serotonin, dopamine, noradrenaline and oxytocin are seen to improve co-operative behaviour and trust (Andari, E. et al., 2010, PNAS, 107, 4389-94; Tse, W. S., & Bond, A. J., 2002, Psychopharmacology, 159, 216-21; Wood, R. M. et al., 2006, Neuropsychopharmacology, 31, 1075-84). 3,4-methylenedioxymethamphetamine (MDMA) elevates mood and induces pro-social behaviour by increasing the levels of all four neurotransmitters (Green, A. R. et al., 2003, Pharmacological Reviews, 55, 463-508). We therefore hypothesised that acutely MDMA would increase co-operative behaviour but then decrease it 3 days later when serotonin reserves are depleted. In a naturalistic study, 17 MDMA users were assessed 45 minutes following acute MDMA on day 0 and when drug free on day 3; 22 non-using controls were tested on the same days. Participants were administered the Public Good Game (PGG), the Dictator Game (DG), the Ultimatum Game – allocator (UGA), and the Ultimatum Game – decider (UGD). The study was approved by the ethical committee of University College London and participants gave written informed consent. In the DG and UGA, signifi cant interactions emerged between group and day (p < .001 and p < .05, respectively). MDMA increased the amount of money given on day 0 but had no effect on day 3. In the PGG and UGD no signifi cant group differences were found. In conclusion, MDMA acutely increases co-operative behaviour suggesting it could aid psychological therapy. Funding: in house UCL.

TH09

ENVIRONMENTAL ENRICHMENT CAN ACCENTUATE CONDITIONED REWARD INDUCED BY REPRESENTATIVE COCAINE DOSES IN MICE Geuzaine A, Psychology, Univ of Liège, Boulevard du Rectorat, 5 (B32); Liège (Belgium) 4000 [email protected] Tirelli E.Dept of Psychology, Univ of Liège boulevard du rectorat, 5 (B32); 4000 Liège (Belgium)

Several preclinical studies report that animals housed in enriched environments (EE) can exhibit reduced behavioural responsiveness to several addictive drugs and can also reverse cocaine seeking (review: Solinas et al. 2010, Progress in Neurobiology, 92:572-592;). However, the few available studies are confl icting. In fact, several weeks of EE beginning after weaning can either facilitate or abolish ulterior conditioned reward/place preference (CPP) in rats and mice, depending on the study (i.e: Solinas et al, 2008, Neuropsychopharmacology, 1-10; Stairs et al. 2009, Pharmacology, Biochemistry and Behaviour, 92:377-382; Green et al 2010, Biological Psychiatry, 67: 28-35;). The purpose of our study was to reassess the infl uence of a complex EE, administered either before or after CPP acquisition, on conditioned reward induced by representative doses of cocaine (5, 10 and 20 mg/kg). In a fi rst set of experiments, groups of four 28-day-old (preadolescent) C56BL/6J mice were housed in an EE (large cages 60x38x19.5cm, toys, pipes, hammocks, nesting material, a running wheel, items periodically replaced) over 10 weeks prior to acquisition and expression of cocaine-induced CPP. Control mice were housed in a standard environment (SE: four mice in a small cage 33x15x13cm, without objects). In a second set of experiments, CPP acquisition and CPP expression test were performed 30 days apart, an interval during which adult mice were housed in one of these two differential environments (all mice being maintained in SE conditions before and during CPP acquisition). ANOVAs were performed on CPP-scores and planned/post-hoc comparisons were used in order to assess any relevant differences between experimental groups. Statistical signifi cance was conventionally set at P<0.05. EE administered before acquisition robustly accentuated CPP expression to a comparable extent for the three doses of cocaine, confi rming several studies and disconfi rming others. One explanation to our results could be that mice maintained in EE before CPP acquisition formed a stronger association between context and cocaine, an effect that has been shown in many studies where EE facilitated pavlovian/spatial learning and neuroplasticity. We have also found (for the fi rst time) that mice housed in EE after CPP acquisition still expressed a clear-cut CPP, disconfi rming (for three cocaine doses) previous studies reporting an inhibitive effect of EE on CPP expression induced by 10 mg/kg cocaine. Obviously, inconsistencies in EE effects could result from between-laboratory variability in procedures. In fact, the available results together suggest that interactions between environments and cocaine effects are far from being satisfactorily characterized. (This research was supported by a Liège University grant) ABSTRACTS A71

TH10

INVESTIGATING THE PROPERTIES OF OBSESSIVE COMPULSIVE SMOKING IN FREQUENT SMOKERS; THE ROLE OF IMPLICIT ATTENTIONAL BIAS AND EXPLICIT VALENCE Hindocha C, Div of Psychology and Language Sciences, Univ College London, Gower St, London WC1E 6BT [email protected] Freeman TP(1), Curran HV(1) (1) Clinical Psychopharmacology Unit, Research Dept of Clinical, Health and Educational Psychology, Univ College London, WC1E 6BT.

Attentional bias is a well documented process in addiction but its precise role is yet to be determined. According to incentive-sensitization theory (Robinson et al, 2003, Addiction. Annu. Rev. Psychol., 54, 25–53) attentional bias refl ects drug ‘wanting’ and should progressively rise alongside elevated use of the drug. In contrast, other theories (e.g. Di Chiara et al 2000, European Journal of Pharmacology 393, 295-314) suggest that the early development of addiction is characterised by goal driven and incentive-based response to drug-related stimuli. However, this subsequently becomes more habit-driven and automatic (i.e. compulsive). Previous studies have addressed these competing views using crude measures of smoking (dependence, cigarette consumption), this study aimed to employ an index closer to the clinical construct of compulsive smoking behaviour using the Obsessive Compulsive Smoking Scale (OCSS; Hitsman et al, 2010 Psychopharmacology, 211, 377-87) which includes factors of ‘preoccupation with smoking’ and ‘compulsive drive. Method: This study assessed 40 smokers (mean age: 22.1, cigarettes/day: 13 (light)) on the OCSS, tobacco dependence (Fagerstrom Test of Nicotine Dependence), measures of implicit ‘wanting’ (the modifi ed Stroop task, dot probe task) and a measure of explicit ‘liking’ (picture rating task). Separate between-subjects analyses using median splits were used to compare groups with low versus high ‘preoccupation with smoking’ and ‘compulsive drive’. Results: On the modifi ed Stroop task, no differences were found between high preoccupation and low lreoccupation smokers. In contrast, low compulsive drive smokers showed more of an attentional bias on this task than high compulsive drive smokers (F(1,38)=3.774, p=0.059). Analysis of explicit valence ratings indicated that smoking-related images were more pleasant among individuals with high preoccupation compared to low preoccupation (F(1,38)=6.008, p=.019). No effects emerged from the dot probe task. A relationship between compulsivity and attentional bias (‘wanting’) is seen in the current results, however, in the opposite direction to that hypothesised by the incentive-sensitization theory. These results suggest that the low compulsivity smokers found drug words more salient then neutral words suggesting that they may be tapping into incentive-related behavioural processes. In contrast, highly compulsive smokers with little control over smoking may be controlled by habit and thus less vulnerable to interference by smoking-related stimuli. In line with evidence that suggests ‘liking’ can occur in the absence of ‘wanting’, we found that preoccupation related to explicit valence of smoking images. The current research highlights the need for research into the pleasurable aspects of obsessive- compulsive smoking.

TH11

EFFECTS OF PLAIN TOBACCO PACKAGING ON VISUAL ATTENTION TO HEALTH WARNINGS IN ADOLESCENT SMOKERS AND NON-SMOKERS Maynard OM, School of Experimental Psychology, Univ of Bristol, 12a Priory Road, Bristol BS8 1TU [email protected] Munafò MR(1), Leonards U(1) (1)Univ of Bristol,12a Priory Rd, Bristol, BS8 1TU

Introduction: Previous research in adults indicates that plain packaging increases visual attention to health warnings in adult non-smokers and weekly smokers, but not daily smokers. The present research partially replicates this study, but in adolescents aged 14-19 years. Methods: A convenience sample comprising never smokers (n = 24), experimenters (n = 34), weekly smokers (n = 13) and daily smokers (n = 14) was recruited from three schools in Bristol, UK. Number of eye movements to health warnings and branding on plain and branded packs was measured, to directly index visual attention. Results: A 4 x 2 x 2 mixed model ANOVA of number of saccades, with smoking status as a between-subjects factor and location of eye gaze and package type as within-subjects factors, indicated a three-way interaction [F(3, 83) = 3.04, P = .033]. Further analyses indicated the presence of a package type x location interaction among experimenters [F(1, 33) = 17.62 P < 0.001] and weekly smokers [F(1, 12) = 4.91, P = 0.047] but not among never smokers [F(1, 25) = 0.24, P = 0.63] or daily smokers [F(1, 13) = 0.87, P = 0.37]. In experimenters and weekly smokers, this interaction refl ected an equal number of eye movements towards the health warnings and branding on branded packs [experimenters: t(33) = .41, P = .683], [weekly smokers: t(12) = .56, P = .583], but more eye movements towards health warnings on plain packs [experimenters: t(33) = 2.69, P = .011], [weekly: t(12) = 2.25, P = .044]. Among never-smokers, a main effect of location was observed, [F(1, 25) = 6.95, P = .014], refl ecting more eye movements towards the health warnings than the branding. No main effect of pack type or location was observed in daily smokers. Conclusions: These results partially replicate the fi ndings in adults, indicating that among light and non-established smokers, plain packaging increases visual attention to health warnings and away from branding. Perhaps indicative of their decision not to smoke and therefore reinforcing their views, never smokers attend the health warnings preferentially on both types of packs. By contrast, daily smokers, even relatively early in their lives as smokers, seem to be resistant to the health warnings on the plain packages. Funding: UK Centre for Tobacco Control Studies, Economic and Social Research Council.

TH12

EFFECTS OF 7.5% CARBON DIOXIDE CHALLENGE ON PHYSIOLOGICAL AND SUBJECTIVE STRESS RESPONSES IN DAILY CIGARETTE SMOKERS AND NON-SMOKERS Anderson MH, Experimental Psychology, Univ of Bristol, 12a Priory Rd, Bristol BS8 1TU [email protected] Attwood A, Munafò MR, Experimental Psychology, Univ of Bristol, 12a Priory Rd, Bristol BS8 1TU

Cigarette smokers often report that smoking is anxiolytic, but tend to show greater levels of stress than non-smokers. It has been suggested that the anxiolytic effects of smoking are due to a reversal of nicotine withdrawal syndrome and exposure to stress has been identifi ed as a risk factor for relapse. To explore the relationship between smoking and stress, we compared the responses of smokers and non-smokers to a 7.5% carbon dioxide (CO2) challenge, which acts as a robust anxiogenic stimulus. Twenty-four (50% male) non-deprived daily smokers and non-smokers underwent two 20-minute inhalations of medical air and 7.5% CO2-enriched air (order counterbalanced). Physiological measures of heart rate and blood pressure, and subjective measures of mood and anxiety (Spielberger State-Trait Anxiety Inventory, Positive and Negative Affect Schedule, visual analogue scales) were taken after each inhalation. There were signifi cant gas × smoking group interactions on systolic (F [1, 22] = 7.81, p = 0.011) and diastolic (F [1, 22] = 4.63, p = 0.043) blood pressure. After CO2 inhalation non-smokers, but not smokers (ps > 0.11), showed signifi cantly higher systolic (t [11] = 6.01, p < .001) and diastolic (t [11] = -2.67, p = 0.022) blood pressure, compared to air. As expected, self-report ratings of anxiety and negative mood were higher and positive mood was lower after CO2 compared to air. Consistent with the physiological data, subjective measurements indicated that reactivity to the gas was greater in non-smokers than smokers, which reached or approached signifi cance for ratings of “happy” (p = .014), “relaxed” (p = .058) and “worried” (p = .076). These data explored the effects of smoking status on the response to a physiological stress challenge, and suggest that non-deprived smokers may be less responsive to a stressor than non-smokers. This supports an anxiolytic effect of recent smoking, which may maintain smoking behaviour and precipitate relapse, particularly during a stressful event. Future research will examine whether stress reactivity in smokers is heightened during nicotine withdrawal. Funded by the National Alliance for Research on Schizophrenia and Depression A72 ABSTRACTS

TH13

THE EFFECT OF EXTINCTION ON PAVLOVIAN TO INSTRUMENTAL TRANSFER IN SMOKERS Retzler CA, School of Psychology, Univ of Nottingham, University Park Nottingham NG7 2RD [email protected] Hogarth L, School of Psychology, Univ of New South Wales, Sydney NSW 2031

A Pavlovian to instrumental transfer (PIT) task was utilized to investigate the infl uence of Pavlovian cues on an instrumental behaviour in daily and non-daily smokers. Participants were trained on four arbitrary Pavlovian cues, of which two predicted cigarette and two predicted chocolate outcomes. Subsequently one chocolate and one cigarette cue were extinguished. Participants then learned an instrumental discrimination in which keyboard responses were paired with either cigarette or chocolate outcomes on a 50% reinforcement schedule. In the fi nal transfer stage the cues were presented followed by a choice between the two keys. The cues elicited a bias for the response that had earned the same outcome as the current cue. This outcome specifi c transfer effect was not sensitive to extinction of either the cigarette or chocolate cues. These fi ndings add to previous animal work, suggesting that extinction does not reduce cue elicited responding in the PIT task, and have implications for treatments involving cue exposure. This work was fi nancially supported by an MRC grant to Lee Hogarth (# G0701456) at the University of Nottingham.

TH14

SELF-CONTROL IN FORMER SMOKERS THAT HAVE SUCCESSFULLY MAINTAINED LONG TERM ABSTINENCE Butler K, Centre for Biomedical and Health Science Research, School of Pharmacy and Biomolecular Sciences, Univ of Brighton, Huxley Bldg, Lewes Road, Brighton BN2 4GJ [email protected] Rusted J(1), Gard P(2), Jackson A(2) (1) Behavioural and Clinical Neuroscience, School of Psychology, Univ of Sussex (2) Centre for Biomedical and Health Science Research, School of Pharmacy and Biomolecular Sciences, Univ of Brighton

‘Top-down’ self-control may be required to protect a former addict from ‘bottom-up’ driven processes that can lead to relapse. However, it remains unclear which specifi c aspects of self-control are important for the maintenance of abstinence. While recent behavioural data suggests inhibitory control does not improve with 3 months of abstinence (Dawkins et al. 2009, Addiction, 104(5):pp850-8), neural activation during performance monitoring is enhanced in former smokers with long term abstinence compared to both current and never smokers (Nestor et al. 2011, NeuroImage, 56(4):pp2258-75). This suggests that performance monitoring as opposed to inhibitory control may be important for relapse resilience. This study compared 15 former smokers (pre-quit smoking levels of ≥ 10 cigarettes per day; mean 20.67 and abstinent for ≥ 12 months; mean 47.17 months) with 15 never smokers (≤ 5 lifetime cigarettes; mean 1.67) on a range of self-control indices (inhibitory control (GoStop Task), performance monitoring (GoStop and Iowa Gambling Tasks), risk taking (Cambridge Gambling Task) and loss aversion (Coin Flip Task)). Data were analysed with t-tests/mixed-design ANOVA or non-parametric alternatives as appropriate. Compared to never smokers, former smokers made more commission errors on the GoStop Task (p = 0.005) refl ecting impaired inhibitory control in this group. On the Iowa Gambling Task, former smokers showed poorer learning than never smokers on one of the disadvantageous decks across the fi ve 20 trial blocks of the task (p = 0.005) and were also slower to learn the deck contingencies, having a smaller performance score (difference between advantageous and disadvantageous deck selections) at the second 20 trial block compared to never smokers (p < 0.05). Risk taking in the Cambridge Gambling Task did not differentiate former smokers from never smokers. However, greater loss aversion was found in former smokers relative to never smokers (p < 0.05). This study shows that indices of self-control differentiate never and former smokers and that former smokers show impairment in aspects of self-control even after long durations of abstinence. Furthermore, loss aversion may be an important factor contributing to the ability of former smokers to maintain long term abstinence. Future longitudinal studies are warranted to determine if elevated loss aversion predicts or is a consequence of successful long term abstinence. KB is in receipt of a University of Brighton Studentship

TH15

EFFECTS OF SMOKING ABSTINENCE ON ATTENTIONAL BIAS FOR EMOTIONAL CUES Adams S, Experimental Psychology, Univ of Bristol, 12a Priory Road, Bristol BS8 1TU [email protected] Brandon M (1), Johnson A (1), Parker S (1), Attwood AS (1), Munafò MR (1) (1) Univ of Bristol, Experimental Psychology, 12a Priory Road, Bristol, BS8 1TU

Nicotine has been shown to enhance the positive value of other stimuli. Specifi cally, nicotine is suggested to modulate attentional bias to emotional stimuli. Here we investigated the effects of smoking abstinence on attentional bias to positive and negative stimuli. In our fi rst experiment weekly smokers (n =45) were randomised to either be nicotine abstinent for 12 hours or not. Participants completed a visual probe task, including positively (happy) and negatively (sad) valenced facial expressions, paired with neutral facial expressions. Participants identifi ed characteristics of a probe that replaced the emotional stimulus on 50% of trials (valid condition) and neutral stimulus on 50% of trials (invalid condition). Data were analysed within a 2 x 2 x 2 design, with abstinence state (abstinent, non-abstinent) as a between-subjects factor, and stimulus type (positive, negative), and validity (valid, invalid) as within-subject factors. A signifi cant interaction between validity x abstinence state (F [1, 43] = 6.29, p = 0.016, η2 = 0.13) was observed. Participants in the non-abstinent condition were faster to respond to probes replacing emotional stimuli compared to those replacing neutral stimuli. Whereas participants in the abstinent condition were faster to respond to probes replacing neutral stimuli compared to those replacing emotional stimuli. In our second experiment weekly smokers (n =96) were randomised to smoke either a cigarette containing nicotine or a denicotinised cigarette before completing the visual probe task as described above. Participants were overnight nicotine abstinent. Data were analysed as above, but with a between-subjects factor of nicotine (nicotine, no nicotine). A signifi cant interaction between validity x nicotine (F [1, 94] = 3.97, p = 0.049, η2 = 0.04) was observed. Participants in the nicotine condition were faster to respond to probes replacing emotional stimuli compared to those replacing neutral stimuli. Whereas participants in the no nicotine condition were faster to respond to probes replacing neutral stimuli compared to those replacing emotional stimuli. Smoking abstinence may disrupt attention towards emotional stimuli. Reduced value of affective cues during nicotine abstinence may be a potential mechanism for novel smoking cessation interventions. SA, ASA and MRM are members of the UKCTCS, a UKCRC Public Health Research: Centre of Excellence. Funding from British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, and the National Institute for Health Research, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. SP was supported by a scholarship from the Nuffi eld Foundation. ABSTRACTS A73

TI01

METHYLPHENIDATE SIGNIFICANTLY REDUCES LAPSES OF ATTENTION DURING ON-ROAD HIGHWAY DRIVING AND IMPROVES VEHICLE CONTROL (SDLP) Cheung CW, Div of Pharmacology, Utrecht Univ, Universiteitsweg 99, Utrecht, The Netherlands 3584CG [email protected] Cheung CW (1), van Seyen M (1), Olivier B (1), Roth T (2), Verster JC (1) (1) Utrecht Univ, Div of Pharmacology, Universiteitsweg 99, 3584CG, Utrecht, The Netherlands; (2) Sleep Disorders and Research Center, Henry Ford Health System, Detroit, Michigan, U.S.A.

Introduction: Lapses of attention are characteristic of patients with Attention Defi cit Hyperactivity Disorder (ADHD) and as such may impair performance of daily activities. Moreover, they may also compromise safety in potentially dangerous activities such as driving a car. To examine the scope of this problem, data from an on-the-road driving study (Verster et al. 2008, J Psychopharmacol 22: 230-239) was re-analyzed to determine lapses in untreated patients with ADHD and determine to what extent treatment with methylphenidate improves attention. Methods: Patients with ADHD (N=17) participated in a double-blind crossover study to comparing driving performance after treatment with methylphenidate (their usual dose, ranged from 10-30 mg) and placebo. A 100-km on-the-road driving test was performed on a public highway in normal traffi c. Patients were instructed to drive with a steady lateral position and constant speed (95 km/h). The Standard Deviation of Lateral Position (SDLP), i.e. the weaving of the car, was computed as traditional outcome measure of vehicle control. Lapses of attention were defi ned as changes of lateral position >100 cm for at least 4 seconds. The number of lapses, maximum lateral deviation, and total time of lapses of attention were computed. Patients also completed the Conners Adult ADHD Rating Scale (CAARS). Results: SDLP results showed that driving was signifi cantly better (p = 0.012) with methylphenidate (SDLP = 18.5 cm) when compared to placebo (SDLP = 20.6 cm). The number of patients showing lapses was 1 (5.9 %) after methylphenidate and 9 (52.9 %) after placebo. The majority of lapses occurred in the second half of the driving test. Relative to placebo, methylphenidate signifi cantly (p = 0.024) reduced the number of lapses (2 versus 24, respectively). The total duration of combined lapses was signifi cantly (p = 0.039) longer after placebo (15.0 s) when compared to methylphenidate (1.8 s). The maximum lateral deviation during lapses did not differ between methylphenidate (+125 cm) and placebo (+128 cm). ∆SDLP and ∆number of lapses (treatment-placebo difference) correlated signifi cantly with each other (r = 0.67, p = 0.003). Patients’ attention scores on the CAARS correlated signifi cantly with ∆SDLP (r = 0.67, p = 0.004) and ∆number of lapses (r = 0.53, p = 0.030). Conclusions: Methylphenidate signifi cantly improves driving ability of patients with ADHD, and signifi cantly reduces the number of lapses of attention experienced during highway driving. Acknowledgment: the study was fi nanced by Utrecht University.

TI02

PROFILES OF LISDEXAMFETAMINE, METHYLPHENIDATE AND MODAFINIL IN RATS TRAINED TO DISCRIMINATE D-AMFETAMINE FROM SALINE Heal DJ, RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF [email protected] Gosden J (1), Slater N (1), Hackett D (2) (1) RenaSci Ltd, BioCity, Pennyfoot St, Notts NG1 1GF (2) Shire Pharmaceuticals Limited, Basingstoke RG24 8EP

Background: Lisdexamfetamine (LDX; Vyvanse®) is a prodrug metabolised in red blood cells to the stimulant, d amfetamine (d AMF) (Pennick 2010, Neuropsychiat Dis Treat 6:317) and methylphenidate (MPH) and modafi nil (MDF) are also stimulants. MPH is a Controlled Drug in the UK, but MDF is not. All have been shown to be effective ADHD medications. Studies in drug experienced human volunteers suggest that the unusual pharmacokinetics of LDX may reduce aspects of its liability for abuse (Jasinski & Krishnan 2009a,b, J Psychopharmacol 23:410 and 419). Methods: We have compared the subjective effects of LDX, MPH and MDF in groups of 6-9 female rats trained to discriminate d AMF (0.5mg/kg ip) from saline. LDX and MPH were tested by the oral (po) and intraperitoneal (ip) routes. MDF was tested ip. Results: 15min post-dosing, LDX (0.5-1.5mg/kg po [d-AMF base]) generalised to saline. At 60min, LDX (0.5-1.5mg/kg po) generalised partially to d-AMF (26-74%) at 0.5-1.0mg/kg and fully (≥75%) at 1.5mg/kg. At 120min, these doses of LDX generalised either to saline or partially to d-AMF. 15min after po dosing, MPH (3.0-10mg/ kg) dose-dependently generalised to d-AMF. Switching to the ip route reduced the interval required for LDX (0.5-1.5mg/kg) to be recognised as d-AMF-like, but did not alter its potency. After ip administration, MPH dose-dependently generalised to d-AMF, but the dose required for full generalisation decreased from 10mg/kg po to 3.0mg/kg ip. MDF (50-150mg/kg ip) and (100 200mg/kg ip) generalised partially to d AMF at 30min and 60min, respectively, but the responses showed considerable inter-animal variability. Conclusion: The results show LDX generalises to d-AMF in rats trained to recognise this discriminative cue. However, LDX’s amfetamine- like subjective effects were delayed in onset after po dosing and of relatively short duration. Its potency was not increased by switching to the ip route. In contrast, generalisation to d-AMF occurred rapidly after po or ip administration of MPH and the potency of the drug was increased 3-fold when dosing was switched to ip. The subjective effects of MDF were recognised as somewhat d AMF-like. LDX and MDF were similar by virtue of their delayed effects and partial generalisation results. These data are consistent with Jasinski’s human fi ndings. They suggest that the stimulant potential of LDX may be similar to MDF.

TI03

A MICRODIALYSIS AND BEHAVIOURAL COMPARISON OF LISDEXAMFETAMINE METHYLPHENIDATE AND MODAFINIL IN FREELY- MOVING RATS Heal DJ, RenaSci Ltd, BioCity, Pennyfoot Street, Nottingham NG1 1GF [email protected] Rowley H(1), Kulkarni R(1) , Hackett D(2) (1) RenaSci Ltd, BioCity, Pennyfoot St, Nottingham NG1 1GF (2) Shire Pharmaceuticals Limited, Basingstoke RG24 8EP

Background: Lisdexamfetamine (LDX) is a prodrug that is metabolised to the stimulant, d-amfetamine (d-AMF), in red blood cells (Pennick 2010, Neuropsychiat Dis Treat 6:317) and methylphenidate (MPH) and modafi nil (MDF) are also stimulants. All are effective ADHD medications. Methods: The Culex Bambino automatically collects samples from dual microdialysis probes and measures locomotor activity in freely-moving rats. LDX (d-AMF base = 0.5, 1.5, 4.5mg/kg po) and MPH (3, 10, 30mg/kg po) were compared at pharmacologically equivalent doses based on generalisation to d-AMF in rat drug discrimination testing. MDF was tested at 100, 300, 600mg/kg po. Effects on extracellular noradrenaline (NA), dopamine (DA) and 5 HT in prefrontal cortex (PFC) and striatum (STR) and locomotor activity were compared ≤5hr post-dose. Results: In PFC, LDX dose-dependently and signifi cantly (p<0.05) increased effl ux of NA (≤529% of baseline) and DA (≤296%), and at the highest dose, 5-HT (≤284%). MPH increased NA (≤261%; ≤289%) and DA (≤217%; ≤343%) at mid and high doses, but only DA (≤202%) at low dose. Low dose MDF had no effect, but the mid and high doses increased NA (≤167%; ≤321%) and DA (≤214%; ≤197%). In the STR, LDX dose dependently increased DA (≤364%) and 5-HT (≤359%). MPH (3.0mg/kg) did not increase DA or 5-HT in STR. MPH produced small (≤131%) and substantial (≤243%) increases in DA at 10 and 30mg/kg. Mid and high dose MDF increased DA (≤128%; ≤137%), but not 5-HT. Low dose MDF was without effect. The actions of MPH and MDF in PFC and STR usually reached a peak at 45 60min, but after LDX it was later 75 120min. The effects of LDX were larger and more sustained than MPH or MDF. LDX did not signifi cantly enhance locomotor activity at 0.5mg/kg or 1.5 mg/kg except at two time-points. A small sustained increase (≤3.6/15min) was seen at 4.5mg/kg. All doses of MPH produced locomotor activation (≤4.7/15min) as did the two highest doses of MDF (≤3.32/15min). Conclusion: LDX has larger and more sustained enhancing effects on NA and DA effl ux in PFC and STR than MPH or MDF. The fi nding that substantial increases in STR DA can be achieved without marked locomotor activation predict LDX will have a good separation between effi cacy and stimulant adverse events than MPH or MDF. A74 ABSTRACTS

PD01

EXAMINING THE ROLE OF DOPAMINE D2 AND D3 RECEPTORS ON BEHAVIOURAL CHANGES IN THE SOCIAL ISOLATION REARED RAT- A NEURODEVELOPMENTAL MODEL OF SYMPTOMS OF SCHIZOPHRENIA Watson DJG, School of Biomedical Sciences,Univ of Nottingham, E Floor, Medical School, Queen’s Medical Centre, Nottingham NG7 2UH David.Watson@ nottingham.ac.uk Loiseau F(2), Marsden CA(1), Millan MJ(2) and Fone KCF (1) (1) School of Biomedical Sciences, QMC, Univ of Nottingham, Nottingham, NG7 2UH; (2) Institut de Recherches Servier, Dept of Psychopharmacology, 125 Chemin de ronde, 78290, Croissy-sur-Seine, Paris, France

Exposure to a range of adverse environmental factors during neurodevelopment is thought to be a risk for the development of psychiatric disorders, such as schizophrenia in later life; an affect which may be enhanced in genetically predisposed individuals. While there are several preclinical models of schizophrenia, each with their own degree of validity, social isolation rearing of rats is one of the few that replicates the neurodevelopmental onset of the disease. Rearing rats in social isolation from weaning (PND 24) produces a complex syndrome of irreversible changes in behaviour (including cognitive dysfunction), neurochemistry and neuroanatomy, resembling those seen in schizophrenia. These changes occur at different rates but are typically seen within six weeks of isolation. Current antipsychotics bind to a multitude of receptor targets but all have affi nity for dopamine D2 and D3 receptors, with little selectivity between the two. Our work has examined the role of dopamine D2 and D3 receptors on the behavioural changes seen in social isolation reared rats by using selective ligands. The dopamine D3 receptor antagonists, S33138 and S33084, have approximately 25 and 100-fold selectivity over other receptor targets respectively, while L741,626 is a selective dopamine D2 receptor antagonist. Acute administration (s.c. 30min pre- treatment) of both S33138 (0.16 and 0.63mg/kg) and S33084 (0.16mg/kg) reverses social isolation-induced impairments in the novel object discrimination task (NOD) using a 2h intertrial interval. Conversely acute administration of L741,626 (0.63mg/kg) has no effect on the social isolation-induced impairment but impairs group housed controls who when treated with vehicle were able to complete the task. Further work using group-housed rats and a variable intertrial interval has confi rmed our fi nding that dopamine D3 receptor antagonism improves cognitive function, while in contrast dopamine D2 receptor antagonism impairs cognition. Moreover, acute treatment with a selective dopamine D3 receptor agonist, PD128,907 (2.5 and 10.0μg/kg), impaired performance in NOD. Additionally we have previously shown using structural MRI, changes in the volume of the prefrontal cortex of social isolation reared rats; this work has been extended to examine the effect of selective dopamine D3 receptor antagonists on the fMRI BOLD response. This work illustrates the social isolation reared rat as a useful neurodevelopmental model of schizophrenia. Furthermore it demonstrates the opposing roles of dopamine D2 and D3 receptors in cognition and supports the potential for targeting the dopamine D3 receptor to treat cognitive dysfunction in schizophrenia. This work was supported by Institut de Recherches Servier.

PD02

ANIMAL MODEL OF AUTISM INDUCED BY PRENATAL EXPOSURE TO VALPROIC ACID:NOVEL IMPLICATIONS Schneider T, Experimental Psychology, Univ of Oxford, South Parks Road, Oxford UK, OX1 3UD [email protected]

Autism is a neurodevelopmental disorder characterised behaviourally by impairments in three core domains: social interaction, verbal and nonverbal communication, and restricted, repetitive patterns of behaviour, interests, and activities appearing before the age of three (DSM-IV, 1994). Despite its high heritability, only approximately 10% of autism cases can be traced to a known genetic aberration (Barton & Volkmar, 1998, J. Autism Dev Disord, 28:273-278). A study of patients in the Swedish thalidomide registry revealed that about 30% of children exposed to thalidomide on the 20–24th day of gestation became autistic (Strömland et al, 1994, Develop Med Child Neurol, 36:351–356). Since thalidomide does not have the same teratogenic effect in rodents as in primates, valproic acid (VPA) was used to injure rats’ brainstems in utero (Rodier et al, 1996, J Comp Neurol, 370:247–261). Offspring of female rats injected with VPA on the 12th day of gestation show several brain abnormalities, resembling those found at autopsy and in brain-imaging studies of autistic patients as well as long-term behavioural defi cits including decreased frequency of and increased latency to social behaviours; locomotor and repetitive, stereotypic-like hyperactivity combined with lower exploratory activity; increased anxiety; lower sensitivity to pain; increased susceptibility to pentylenetetrazole-induced but not audiogenic seizures, and diminished acoustic prepulse inhibition (Schneider et al, 2005, Neuropsychopharmacology, 31:36-46). VPA rats express also molecular and immunological aberrations resembling those observed in autism, e.g., altered functioning of opioidergic, serotonergic, dopaminergic, and glutamatergic systems, and decreased cellular immunity. Interestingly, observed aberrations were found in males only and were reversed by environmental enrichment procedure (Schneider et al, 2006, Neuropsychopharmacology, 31:36-46; Schneider et al, 2008, Psychoneuroendocrinology, 33:728-740). Similarities in behavioural, anatomical, biochemical and immunological pathology in autism and VPA rats suggest the utility of the VPA rodent model of autism for defi ning common pathways for dysregulation of normal developmental patterns and assessing the time course and sources of vulnerability to that still incurable disorder. I will show recent empirical and theoretical applications of VPA model towards better understanding and potential new treatments for autism.

PD03

MAM E17 MODEL: THE LILLY EXPERIENCE SO FAR Malik NN, Psychiatry, Eli Lilly, Erl Wood Manor Windlesham, Surrey, UK GU20 6PH [email protected]

Schizophrenia is a lifelong disorder that affects 1% of the population worldwide and often begins in late adolescence or early adulthood. It is characterised by positive, negative and cognitive symptoms. Negative and cognitive defi cits are more diffi cult to measure in rodents but may be a better predictor than positive symptoms of the long-term outcome following treatment of patients with schizophrenia. One of the major challenges in schizophrenia research is the development of suitable models for these aspects of the disorder. In this regard, one model we have studied in some detail is the methylazoxymethanol (MAM) neurodevelopmental model. MAM is a neuro-specifi c antimitotic agent that prevents cells from dividing for a short time after injection. It can be dosed intraperitoneally to pregnant dams on gestational day 17, theoretically causing neuroanatomical and behavioural alterations in offspring that are akin to core symptoms seen in schizophrenia. Our fi ndings confi rm that MAM model offspring exhibit several neurodevelopmental and pathological changes that bear similarities to schizophrenia. These include reductions in cortical thickness and hippocampal size, and enlargement of ventricles. Electrophysiological function and sleep are also affected, shown by changes in ES-coupling, sleep bout length and delta power. Behavioural consequences of MAM, largely emergent after puberty, include increased locomotor responsiveness to NMDA antagonist administration, and also pre-pulse inhibition and cognitive fl exibility defi cits. However, the robust neuropathological and neurophysiological fi ndings found in the MAM E17 model do not always translate into behavioural defi cits. This is of critical consequence for model validation and use in discovery research. The variability in behaviour effects will be discussed, taking into consideration factors such as litter effects, study design and statistical analysis. Overall, our data suggests that maternal treatment with MAM on embryonic day 17 leads to persistent alterations in the adult offspring of CD rats that are relevant for modelling aspects of schizophrenia - but revised methods for study design and statistical analysis are crucial to avoid misinterpretation of fi ndings. This work was funded by Eli Lilly & Company Limited. ABSTRACTS A75

PD04

CROSS-FOSTERING IN RODENTS; A MODEL OF PSYCHIATRIC DISEASE? Hall SP, Inst of Neuroscience, Newcastle Univ, ION (Cookson building) Medical School Framlington Place, Newcastle Univ NE2 4HH [email protected] Racca C(1), Whittington MA(1), Cunningham MO(1). Inst of Neuroscience, Medical School, Framlington Place, Newcastle Univ, NE2 4HH

Cross-fostering alters responses to stress in adulthood and there is a strong link between early life stress and the subsequent development of psychosis (Jones et al, (1994) Lancet (344) 1398-1402; Isohanni et al, (2001) Sch.Res. (52) 1-19). Defi cits in gamma frequency oscillations are known to play a major role in the development of psychosis (3Woo et al, (2010) Hav.Rev.Psyc. (18) 173-189). We examined the impact of cross-fostering on gamma oscillations in regions of the forebrain implicated in the neurobiology of psychosis. Extracellular fi eld potential (LFP) recordings were carried out in LII/III of the medial entorhinal cortex (mEC), and the hippocampus (HPC), in combined EC-hippocampal brain slices (450μm) prepared from cross-fostered or natural adult CD rats. Gamma oscillations were induced by bath application of kainate (1-500nM). In response to increasing kainate concentrations there were signifi cant differences (p<0.01, n=9) in the peak frequency of gamma oscillations in the mEC (natural; 53.6±3.6Hz, cross-fostered; 40.9±2.8Hz), but not in the HPC (p>0.05, n=8). To assess the degree of inhibition in LII/III of the mEC, mono-synaptic inhibitory post-synaptic potentials (IPSPs) were elicited by electrical stimulation. Principal neuron IPSPs were signifi cantly larger (p<0.05, n=15) in cross-fostered (LII stellate, 25.2±1.7mV; LIII pyramidal, 14.0±1.1mV) when compared with natural (LII stellate, 16.8±1.9mV, LIII pyramidal 9.1±1.3mV). Post-hoc immunocytochemistry revealed a signifi cant increase (p<0.001, n=19) in parvalbumin positive GABAergic interneurons in LIII of the mEC (natural; 50.9±4.5, cross-fostered; 89±10.1) but not in the HPC. These results indicate EC gamma oscillations and the interneuron populations underlying this activity are altered in cross-fostered animals. Work funded by the MRC and GSK

SO01

ROBUST AND REPRODUCIBLE RECOGNITION MEMORY DEFICIT IN RATS INDUCED BY SUB CHRONIC PCP: VALIDATION WITH ANTIPSYCHOTICS AND COGNITION ENHANCERS Ballard TM, CNS Discovery, F.Hoffmann-La Roche Ltd, Bldg. 72/150 Grenzacherstrasse, Basel, Switzerland, CH-4070 [email protected] Haman M, CNS Discovery, F.Hoffmann-La Roche Ltd., Grenzacherstrasse, CH-4070 Basel, Switzerland.

Sub chronic administration of phencyclidine (scPCP) to rats results in cognitive defi cits and neuropathological changes which model some aspects of schizophrenia (Neill et al. 2010, Pharmacology & Therapeutics, 128, 419-432). The aim of the current study was to investigate the effect of scPCP on recognition memory in rats and to assess the effects of antipsychotics and cognition enhancers. Male Lister hooded rats were administered either vehicle (0.9% saline) or PCP at 3 mg/kg i.p. twice daily for 7 days, followed by 7 days washout. In week 2, subjects were habituated for 30 min in locomotor activity (LMA) chambers, then administered an acute dose of PCP (5 mg/kg i.p.) and assessed over a 90 min period. In weeks 3, 4 and 5, subjects were tested three times in the object recognition test. Rats were habituated to the test chamber (60 x 60 x 40 cm) for 5 min, 24 h prior to testing. On Trial 1, rats were placed back into the chamber for 3 min and time spent exploring two identical objects was recorded. One hour later, rats were returned to the chamber (Trial 2) for 3 min and time spent exploring a novel and a familiar object was recorded. The discrimination index (novel - familiar / total object exploration) was determined and analysed by one factor ANOVA followed by post hoc Dunnett’s. Compounds were administered prior to Trial 1 (n=10/group): haloperidol (0.1 mg/kg i.p.); risperidone (0.1-0.5 mg/kg i.p).; aripiprazole (0.3-3 mg/kg i.p.); clozapine (0.3-3 mg/kg i.p.); olanzapine (0.1-1 mg/kg i.p.); M100,907, 5-HT2A antagonist (0.03-0.3 mg/kg s.c.); LY354740, mGlu2/3 agonist (6 mg/kg i.p.); donepezil (3 mg/kg p.o.); modafi nil (16-64 mg/kg p.o.). scPCP had no effect on baseline LMA, but resulted in sensitization to acute PCP (p<0.001). Moreover, scPCP induced a signifi cant impairment of recognition memory, which was robust and reproducible during weeks 2-5 of the washout period. Haloperidol (p=0.5), LY354740 (p=0.6) and donepezil (p=1.0) did not have an effect on the recognition memory defi cit. Olanzapine signifi cantly reversed the defi cit (1 mg/kg; p<0.01), whereas clozapine (p=0.06), risperidone (p=0.1) and aripiprazole (p=0.07) did not reach signifi cance. Modafi nil (64 mg/kg; p<0.05) and M100907 (0.3 mg/kg; p<0.01) dose-dependently and signifi cantly reversed the cognitive defi cit. The current data replicates previous fi ndings with modafi nil (Redrobe et al, 2010, Front Psychiatry, 1, 146). In addition, this model shows sensitivity to 5-HT2A antagonism which may partially explain the effects of some of the antipsychotics.

GL1

DRUGS IN THE BRAIN: TRANSFORMING REWARD INTO ADDICTION Volkow ND, Director, National Institute on Drug Abuse, National Institutes of Health, 6001 Executive Blvd., Suite 5274, Bethesda, USA, MD 20892-9581, nvolkow@ nida.nih.gov

Chemicals that activate the reward system are reinforcing to humans (but also to a wide variety of animals from reptiles into humans) including humans. Their supraphysiological activation of the brain reward systems (including dopaminergic activation via D1 and D2 receptors in the nucleus accumbens) is believed to be the starting point for the neurobiological changes that launch the addiction trajectory (including dysregulation of glutamatergic signaling through NMDA and AMPA receptors in limbic regions and frontal cortex). Research on addiction has started to uncover the sequence of events and long-lasting sequelae that can result from the persistent abuse of addictive substances (including nicotine and alcohol). These studies have shown how repeated drug use can target key molecules (both common and specifi c for various drugs types) and brain circuits, and eventually disrupt the higher order processes that underlie emotions, cognition and behavior and that enable and individual to exert self control. Specifi cally preclinical and clinical brain imaging studies have shown that addiction is characterized by an expanding cycle of dysfunction in the brain. The impairment appears to start in the evolutionarily more primitive areas that process reward, but then moves on to other brain regions responsible for more complex cognitive functions. Thus, in addition to reward, addicted individuals can experience severe disruptions in learning (memory, conditioning, habituation), executive (impulse inhibition, decision making, delayed gratifi cation, judgement), cognitive awareness (interoception) and even emotional (mood and stress reactivity) functions. The combined, cumulative impact of addiction on all these circuits results in addicted individuals making poor choices despite awareness of the negative consequences and are unable to delay gratifi cation despite future losses. It also explains why previously rewarding life situations and the threat of judicial punishment cannot stop drug taking and why a medical rather than a criminal approach is more effective in curtailing addiction. In turn this knowledge also informs of strategies for medication development to help buffer the brain dyfunction associated with chronic drug exposures and with addiction. A76 ABSTRACTS

PW1

LIFTING THE VEIL ON ADDICTION VULNERABILITY Ersche KD, Dept of Psychiatry, Univ of Cambridge, Brain Mapping Unit, Herchel Smith Bldg, Cambridge CB2 0SZ [email protected] Jones PS(1), Williams GB(1,2), Smith DG(1), Bullmore ET(1, 3,4), Robbins TW(1) (1) Behavioural and Clinical Neuroscience Inst, Univ of Cambridge, Depts of Experimental Psychology and Psychiatry, Cambridge, UK. (2) Wolfson Brain Imaging Centre, Univ of Cambridge, Cambridge, UK (3) GlaxoSmithKline, Centre for Clinical Investigations, Cambridge, UK (4) Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, UK

Stimulant drugs such as cocaine and amphetamines are popular recreational drugs that are used by up to 56 million individuals worldwide (UNDOC, Word Drug Report 2010 (UN Publications, 2010). Despite their high addictive liability, not everyone who uses them develops dependence, but the risk is increased for individuals with a family history of addiction. This familial aggregation of drug and alcohol dependence suggests that either genetic factors, a shared family environment, or both underlie the increased risk for addiction in some people. The concept of endophenotypes has been used to identify markers of familial risk that are shared by affected patients and their unaffected fi rst-degree relatives (I. I. Gottesman, T. D. Gould, Am J Psychiatry 160, 636 (2003). We aimed to identify endophenotypes for stimulant dependence and compared personality traits and brain structure between 50 adults with stimulant-dependence, their non-dependent siblings and 50 unrelated healthy volunteers who had neither a personal nor a family history of dependence (K. D. Ersche et al., Science 335, 601 (2012). We hypothesized that the sibling pairs would share personality traits and brain abnormalities that have been associated with drug addiction. Indeed, we found signifi cantly higher levels of impulsive and compulsive personality traits in the sibling pairs compared with unrelated healthy volunteers (both P<0.001). The pairs also shared abnormalities in brain regions that have been associated with drug addiction such as the inferior frontal gyrus, the amygdala and the putamen. Our fi ndings shed new light on why the risk of becoming addicted to drugs is increased in people with a family history. Our fi ndings may also suggest that these vulnerability markers would not be seen in individuals without familial risk who have been using cocaine for several years without making the transition to dependence. We therefore investigated personality traits and brain structure in a group of 27 recreational cocaine users who had no personal or family history of dependence using the same methodology. We found a double dissociation between personality traits and brain structure associated with a familial vulnerability and stimulant use. Whilst familial vulnerability was associated with impulsive and compulsive personality traits (both P<0.001) and limbic-striatal enlargement, stimulant exposure was linked with sensation-seeking traits (P<0.001) and abnormalities in orbitofrontal structure. This double dissociation suggests that individuals at high risk for dependence are the ones with both a family history and high levels of sensation-seeking traits. This work was funded by a Medical Research Council and received institutional funds from the Behavioural and Clinical Neuroscience Institute, which is jointly funded by the Medical Research Council and the Wellcome Trust.

PW2

POWER, PRECISION AND PHENOTYPE IN GENETIC ASSOCIATION STUDIES Munafo MR, Experimental Psychology, Univ of Bristol, 12a Priory Road, Bristol BS8 1TU [email protected]

The early promise of candidate gene studies was soon replaced by disappointment when it became apparent that many early fi ndings could not be reliably replicated. We now know much more about the genetic architecture of complex traits – a very large number of common genetic variants, each with very small effects, contribute to the observed heritability of these traits, as well as perhaps some rare and de novo variants of larger effect. Even brain-based phenotypes, which it had been argued might offer a stronger genetic signal, have been shown to conform to the same basic genetic architecture. The current solution is to rely on genome-wide association studies, which are agnostic with respect to the specifi c genetic variants of interest and instead use very large sample sizes, together with stringent statistical criteria, to identify these common variants of small effect. These methods are beginning to yield clear results, particularly in certain areas such as tobacco use where the behaviour is under a close degree of biological control. However, a limitation of the search for ever-larger sample size is that disparate and heterogeneous phenotypes must be combined, which may limit the sensitivity of any resulting analyses. One partial solution may be to seek improved phenotype measurement precision, even if this at the expense of sample size. For example, the well established association between a region on chromosome 15 and heaviness of smoking accounts for 1% of phenotypic variation in cigarettes per day, but up to 5% of phenotypic variation in cotinine levels, the primary metabolite. Individual differences in smoking topography mean that the levels of nicotine extracted from a cigarette differ considerably between smokers, and this appears to be under strong genetic infl uence. These genetic infl uences on tobacco and other substance use phenotypes offer the exciting possibility of conducting causal analyses to establish the causal nature of the observed comorbidity between, for example, tobacco use and depression. This mendelian randomisation approach is predicated on the fact that genotype should be unrelated to confounders which typically plague observational studies, such as age and socioeconomic position. A number of studies are now emerging which use genetic information in this way to explore the causal effects of substance use on psychiatric outcomes.

PW3

DEVELOPING NEUROIMAGING-BASED BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS IN DEPRESSION Fu CHY, Psychological Medicine, Inst of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF [email protected]

A network of limbic-cortical functional changes underlie the affective and cognitive symptoms of depression (Fu et al., 2004; 2008a). The functional abnormalities may be normalised following treatment with pharmacotherapy (Fu et al. 2004, 2007; Walsh et al., 2007) as well as cognitive behavioural therapy (Fu et al., 2008a). Structurally, characteristic hippocampal deformations are already evident in the fi rst episode of depression (Cole et al., 2010, 2011). These research fi ndings have not yet been translated into practical tools, as there are no neurobiological diagnostic or prognostic markers in clinical use for depression, or other psychiatric disorders. We have found that the network of functional neural responses shows high accuracy in identifying individual patients in an acute depressive episode (Fu et al., 2008b). Moreover, cerebral grey matter loss may be predictive of clinical response to pharmacotherapy for an individual patient, prior to the initiation of treatment, while the pattern of neural activity may be predictive of clinical response to psychotherapy (Costafreda et al., 2009a,b; Nouretdinov et al., 2011). There is increasing evidence for a network of regions that is predictive of clinical outcome in pharmacological and psychological treatment studies, as demonstrated by meta-analysis (Fu et al., 2012). These diagnostic and prognostic markers have predictive value at the level of the individual patient and may therefore be of translational value. In particular, they may provide a step towards stratifi ed medicine in depression by predicting clinical response to specifi c treatments. INDEX OF PRESENTING AUTHORS A77

Presenting Author Page Presenting Author Page

Adams S A72 Adewusi ODT A21 Fletcher PC A1 Alford CA A54 Freeman TP A67 Anacker C A51 Fu CHY A76 Anderson MH A16, A71 Gage SH A64 Andreasen JT A29 Gaskin PLR A36 Bailey CP A2 Geuzaine A A70 Bailey SJ A3, A16 Glasper JE A35 Baker LD A55 Godlewska BR A20 Baldwin DS A48 Gozzi A A7 Ballard TM A75 Grant JG A12 Benn A A29 Hall J A10 Bertelsen F A56 Hall SP A75 Bhagwagar Z A6 Handley R A38 Binder EB A4 Harmer CJ A8 Bloomfield MAP A41 Harrison L A22 Bohacek J A11 Hasnaoui SK A43 Bolognesi F A44 Hazelgrove KM A18 Borsini A A20 Heal DJ A61, A73 Bossong MG A28 Hepgul N A49 Brandish EK A34 Herbert J A4 Brugger S A40 Hickman M A3 Bufalino C A20 Hindocha C A71 Butler K A72 Hirst JBF A56 Button KB A44 Horowitz MA A51 Capitao LP A32, A62 Hou R A15 Carhart-Harris RL A28 Howes OD A9 Cattaneo A A19 Hudaib AR A14 Cerit H A13 Inamdar A A65 Chamberlain SR A12 Ismail M A69 Chan KFD A30 Joels M A4 Cheung CW A73 Joules R A59 Clarke HF A5 Kamboj SK A32 Cottin J A16 Kaser M A45 Dachtler J A63 Kenny MA A18 Damany MD A56 King MV A35 Das RK A67 Kleinloog D A36 De Carvalho F A14 Kohli S A66 Deakin JFW A1 Kokras N A17, A60 Di Simplicio M A17 Krystal JH A1 Diaper A A23 Lally N A25 Dissanayake LK A44 Lapiz-Bluhm MD A13 Doyle OM A26 Lawson RP A25 Dudley JA A54 Leandri J A50 Durant CF A21 Lenox-Smith A A48 Erritzoe D A43 Lesch KP A12 Ersche KD A76 Lightman SL A3 Evans SL A28 Loxton K A34 Falcone MA A66 Lubman DJ A42 Fantini E A18 Malik NN A74 Faulkner P A59 Malizia AL A22 Fawcett H A31 Mann K A2 Ferguson B A70 Marsh S A36 Field M A42 Maynard OM A71 Fineberg NA A11 McCabe C A17 Fisher MJ A45 McGonigle J A24 A78 INDEX OF PRESENTING AUTHORS

Presenting Author Page Presenting Author Page

McLean SL A57 Svendal G A53 McNally GP A7 Talat B A33 Mehta MA A8 Tang H A38 Mercuri K A40 Taylor DM A65 Middleton LJ A57 Taylor MJ A49 Mill J A11 Thomas JM A67 Mitchell EN A13 Tomlinson A A30 Mitchelmore RLJ A65 Trist AJ A46 Mondelli V A37 Turton S A69 Moore H A9 Tyacke RJ A27 Moriarty AS A55 van Seyen M A42 Munafo MR A76 van Wel JHP A70 Musaelyan K A50 Vernon AC A37 Nathan PJ A8 Volkow ND A75 Nikkheslat N A52 Wallace J A63 Norbury R A48 Watson DJG A74 O’Brien S A60 Wertz JW A47 O’Hagan CM A15 Wilkinson LS A10 Olarte-Sanchez CM A58 Wing VC A66 O’Leary C A60 Wood BR A23 Owen MJ A10 Wood CM A61 Oyegbami O A54 Yevtushenko OO A52 Paresys L A49 Ziauddeen H A67 Patel MX A39, A53 Zunszain PA A61 Pauls AM A47 Pepper FS A67 Picchioni M A33 Plant DT A47 Preeti G A33 Pringle A A58 Quelch DR A24 Regan CM A57 Retzler CA A72 Reynolds J A41 Rigney U A39 Ring R A46 Roberts RE A27 Robinson ESJ A5 Rock PL A52 Rodgers RJ A67 Roiser JP A5 Rose AK A7 Rybka J A19 Sahakian BJ A9 Schneider T A74 Selvaraj S A26 Shoaib M A6 Shortall SE A69 Solinas M A6 Somal SK A31 Steckler T A2 Stenson GM A63 Stone JM A27 Stuart SA A46 Stumpenhorst K A64