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Poster Session I As Demonstrated by Reduced Levels of KOR Mrna and KOR Binding, to Follow up Initial Findings That Systemic Blockade of M2

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Neuropsychopharmacology (2012) 38, S79–S197 & 2012 American College of Neuropsychopharmacology. All rights reserved 0893-133X/12 www.neuropsychopharmacology.org S79 Monday, December 03, 2012 littermate controls. Like JDTic treated mice, DATCre KOs showed significantly lower levels of potentiation than controls. Conclusions: These studies used two novel lines of KOR KO mice, Poster Session I as demonstrated by reduced levels of KOR mRNA and KOR binding, to follow up initial findings that systemic blockade of M2. Blockade of Kappa Opioid Receptors Reduces Footshock KORs with JDTic reduces startle potentiation after footshock. Effects on Startle Interestingly, constitutive KOR KO mice show equivalent levels of Ashlee Van’t Veer*, Anita Bechtholt-Gompf, Sara Onvani, footshock-potentiated startle compared to wild type littermates, David Potter, Yujun Wang, Elena Chartoff, Uwe Rudolph, whereas KOR deletion restricted to DAT expressing neurons Lee-Yuan Liu-Chen, F. Ivy Carroll, Bruce Cohen, (DATCre KO) was sufficient to reduce potentiated startle following William Carlezon the first two blocks of footshock. This pattern of results suggests that compensatory adaptations occurring outside brain DA Harvard Medical School, Belmont, Massachusetts systems may offset behavioral changes that are caused by KOR deletion within brain DA systems in constitutive KOR KOs. Background: Brain kappa-opioid receptors (KORs) have been Overall, these data implicate KORs of midbrain dopaminergic cells implicated in the behavioral consequences of stress, such as drug in the manifestation of stress, and provide additional evidence that seeking and depressive-like behavior. Previously, we have shown disruption of KOR function reduces stress-induced anxiety-like that systemic KOR antagonism produces anxiolytic-like effects in behavior. JDTic treated mice had acute blockade of KORs, while tests of both conditioned and unconditioned fear. The present KOR KO mice had a lifelong absence of KORs. Thus, the finding studies were designed to further characterize interactions between that systemic KOR antagonism produces anti-stress effects that are KOR systems and stress-induced behavior using footshock as a not seen in the constitutive KOR KO mice suggests the importance stressor, the effects of which can be measured by potentiation of of neuroadaptations occurring during brain development. the acoustic startle reflex. This potentiation was investigated after Keywords: kappa opioid, stress, startle, mouse systemic blockade or constitutive deletion of KORs. Recently, it Disclosure: A. Van’t Veer, Nothing to Disclose; A. Bechtholt- has been shown that stress induces KOR phosphorylation in the Gompf, Nothing to Disclose; S. Onvani, Nothing to Disclose; nucleus accumbens, where KORs are expressed on the terminals of D. Potter, Nothing to Disclose; Y. Wang, Nothing to Disclose; dopamine (DA) neurons originating in the ventral tegmental area E. Chartoff, Nothing to Disclose; U. Rudolph, Part 1: Sunovion (VTA). To characterize the involvement of this specific population Pharmaceuticals, Concert Pharmaceuticals, Part 2: Sunovion of KORs we generated a conditional knockout in which KORs are Pharmaceuticals, Concert Pharmaceuticals, Part 3: Sunovion selectively deleted in DA-containing neurons. Pharmaceuticals, Concert Pharmaceuticals; L. Liu-Chen, Nothing Methods: To study the effects of KOR on stress-induced behaviors, to Disclose; F. Carroll, Nothing to Disclose; B. Cohen, Nothing to mice were designed with loxP sites flanking exon 3 of the KOR Disclose; W. Carlezon, Part 1: The American College of Neuro- gene. This arrangement enables gene inactivation by Cre psychopharmacology, Myneurolab.com. recombinase and generation of our two KOR KO lines. Floxed mice were crossed to either a ubiquitous Cre line (EIIaCre) to generate constitutive KOR KOs or DATCre to generate conditional KOs lacking KORs specifically in DA transporter (DAT)-expres- M3. Imparied Mesolimbic Regulation of Prefrontal Glutamate and sing cells, such as those found in the VTA and substantia nigra Acetylcholine Release Accompanies Cognitive Inflexibility in Two (SN). Knockout of the receptor was confirmed with autoradio- Animal Models of Schizophrenia graphy using a radiolabeled KOR agonist ([H3]U-69593). Further, Michelle Pershing, Dave Bortz, Ana Pocivavsek, Martin Sarter, mRNA analyses were performed on brain tissue samples using Robert Schwarcz, John P. Bruno* qPCR to demonstrate specificity of deletion. To test the effect of The Ohio State University, Columbus, Ohio KOR antagonism on shock-potentiated startle, mice were matched into groups with equivalent baseline startle and given an Background: Executive control, under conditions of enhanced intraperitoneal injection of the KOR antagonist JDTic or vehicle cognitive demands, is mediated by top-down recruitment, by the 24 hr prior to testing to accommodate the slow onset and prefrontal cortex (PFC), of a network that includes the ventral persistent actions of this drug. In the test session, mice received a hippocampus (VH), nucleus accumbens (NAC) and basal fore- baseline startle test followed by ascending footshock amplitudes brain. Several of the cognitive deficits seen in schizophrenia (SZ), (0.2 mA, 0.4 mA, and 0.8 mA) each followed by a startle test. The including, attention and cognitive flexibility, are believed to following day, mice were given a final startle test. KOR KO mice emerge from impaired prefrontal cholinergic and glutamatergic were subjected to the same behavioral protocol without adminis- transmission arising from dysregulations in these cortical- tration of JDTic. Data were analyzed using appropriate ANOVAs subcortical interactions. and significant effects were analyzed using post hoc Bonferroni Methods: Neurochemical and cognitive deficits were compared in tests. Experiments were conducted in accordance with National two neurodevelopmental rat models of SZ: 1) elevated levels of the Institutes of Health and McLean Hospital guidelines for the care endogenous alpha7 nAChR antagonist kynurenic acid (KYNA) and use of laboratory animals. following daily exposure of the dam/litter (GD 14/15-PD21) to mash Results: Autoradiography demonstrated a lack of KOR binding in containing the precursor kynurenine and 2) transient inactivation constitutive KOR KO mice and reduced binding in conditional of impulse flow in VH following bilateral local infusions of TTX DATCre KOs. Further, qPCR demonstrated no detectable KOR during a sensitive period of development (PD7). Testing was mRNA in KOs and reduced KOR mRNA specifically in the VTA/SN conducted in young adults (PD56-80). Mesolimbic stimulation was of DATCre KOs. Blockade of KOR receptors by JDTic attenuated produced with infusions of NMDA (0.05 - 0.3 mg/0.4 mL) into the footshock induced increases in startle. When shocked mice were NAC shell. The mesolimbic regulation of prefrontal glutamate returned to the testing chamber on the following day, JDTic release was measured by a glutamate-sensitive microelectrode pretreated mice continued to show significantly decreased context array and ACh levels using microdialysis. As a measure of conditioning. In comparison, constitutive KOR KO mice had cognitive flexibility, performance in an attentional set-shifting task similar levels of footshock-potentiated startle compared to (ID/ED digging task) was determined, in separate groups of ACNP 51st Annual Conference Abstracts S80 animals, with and without acute pretreatment with an alpha 7 n infusions of the D1/D2 dopamine receptor antagonist a-flupenthixol AChR agonist [galantamine or SSR18711 (both at 3.0 mg/kg, i.p.)]. (0,5,10,or15mg/side) immediately prior to 15-min cocaine seeking Results: Rats exposed to kynurenine during development exhibited test sessions in which each lever press was only reinforced by a 1-sec elevated levels of forebrain KYNA on PD2, PD21, and even as presentation of the CS [FI15(FR1:S)]. The response requirement was adults (long after exposure had stopped). In adult controls, intra- then gradually increased across sessions to a FR10(FR4:S) second- NAC NMDA produced a dose-dependent phasic increase in order schedule in which every forth lever press resulted in a 1-sec CS prefrontal glutamate release as well as a tonic increase in presentation; cocaine and the 20-sec CS were presented on the tenth extracellular ACh levels. NMDA-induced cortical glutamate and FR4 completion. Following 5 training sessions on this schedule, a- ACh release was almost eliminated in rats that had developed with flupenthixol was again infused into the DLS during 15-min cocaine elevated KYNA levels. In addition, these rats exhibited selective seeking tests in which every forth lever press was only reinforced by impairments [reversal (REV) and extra-dimensional shift (EDS)] the 1-sec CS presentation [FI15(FR4:S)]. The response requirement in the set-shifting task which were normalized by pretreatment was then increased to a FI15(FR10:S) second-order schedule in which with galantamine. Similar results were seen following transient cocaine seeking was maintained over 15-min delays by 1-sec CS postnatal inactivation of the VH with TTX. As adults, these rats presentations on every tenth lever press. Following 15 sessions of failed to display the NMDA-induced increases in prefrontal training on this schedule, cocaine seeking tests with intra-DLS glutamate or ACh. They also exhibited deficits in REV and EDS dopamine receptor blockade were again conducted. stages of the behavioral task that were normalized
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  • Whittle-Neuropharm-2013.Pdf

    Whittle-Neuropharm-2013.Pdf

    Neuropharmacology 64 (2013) 414e423 Contents lists available at SciVerse ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model Nigel Whittle a,*, Claudia Schmuckermair a, Ozge Gunduz Cinar b,d, Markus Hauschild a, Francesco Ferraguti c, Andrew Holmes b,d, Nicolas Singewald a a Department of Pharmacology and Toxicology, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80 e 82/III, A-6020 Innsbruck, Austria b Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcoholism and Alcohol Abuse, National Institutes of Health, Bethesda, MD 20852, USA Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences, Bethesda, MD c Department of Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria d Center for Neuroscience and Regenerative Medicine at the Uniformed Services University of the Health Sciences, Bethesda, MD, USA article info abstract Article history: Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse Received 30 March 2012 deficits in fear extinction represent a tractable approach to treating these disorders. We previously re- Received in revised form ported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We 31 May 2012 now demonstrate that weak fear conditioning does permit fear reduction during massed extinction Accepted 6 June 2012 training in S1 mice, but reveals specificdeficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with D-cycloserine (N-methly-D-aspar- Keywords: tate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training.