Early Ventral Hippocampal Lesion Model Eating and Appetite

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Early Ventral Hippocampal Lesion Definition Model Feeding reflects the behavioral response neces- Definition sary for replenishing energy substrates critical for survival, whereas appetite refers to the moti- An animal model in which the ventral hippocam- vational component of this behavior. pal region in rats is lesioned using an excitotoxic agent. This lesion is performed at an early age (typically postnatal day 7). These animals Impact of Psychoactive Drugs develop several schizophrenia-like phenomena in adulthood. Interestingly, most of the symptoms Feeding can be defined as the behavioral response occur after puberty in accordance with the clini- necessary for replenishing energy substrates to cal literature on schizophrenia. maintain energy balance and, ultimately, the survival of all organisms. Predictably, a shortage of Cross-References food sources is associated with increased motivational states that promote food seeking, as well ▶ Schizophrenia: Animal Models as metabolic changes that allow for energy stores ▶ Simulation Models to be amassed in the form of adipose tissue. In general, increases in these motivational states are commonly referred to as appetite (Berthoud Eating and Appetite and Morrison 2008). Feeding can also be elicited by the mere presence of food and, in the absence Alfonso Abizaid1 and Shimon Amir2 of a negative energy state, possibly as an adaptive 1Department of Neuroscience, Carleton behavioral response directed at storing excess University, Ottawa, ON, Canada energy in anticipation of future shortages. 2Department of Psychology, Center for Studies in Clearly, the mechanisms regulating feeding Behavioral Neurobiology, Concordia University, behavior are complex and involve both regula- Montreal, QC, Canada tory and nonregulatory processes. Peripheral signals regulating energy balance. Both food intake and appetite are influenced by Synonyms multiple neural and peripheral signals. These include energy substrates such as glucose, free Energy intake fatty acids, and amino acids; hormones such as

# Springer-Verlag Berlin Heidelberg 2015 I.P. Stolerman, L.H. Price (eds.), Encyclopedia of Psychopharmacology, DOI 10.1007/978-3-642-36172-2 E 570 Eating and Appetite leptin, cholecystokinin (CCK), insulin, and than direct action on aminergic neurotransmitters. ghrelin; and neurotransmitters, including dopa- Rimonabant, a compound that blocks the cannabi- mine (DA), serotonin (5-HT), norepinephrine noid CB1 receptor, has some appetite suppressant (NE), and endocannabinoids. Moreover, drugs properties, although it has been recently rejected that affect these systems are currently used to as an antiobesity medication. Leptin, a hormone curb obesity and treat type II diabetes or to produced by white fat cells, also lowers food increase feeding in pathological conditions that intake and body weight and continues to be con- lead to anorexia and cachexia (e.g., cancer and sidered as a potential drug to treat obesity and chronic renal disease). Finally, drugs used to treat metabolic syndrome (Bray and Greenway 2007). other conditions have side effects that include Allofthesedrugshavebeenreportedtobeeffec- abnormal feeding behaviors (anorexia or overeat- tive in reducing appetite, but their effects are short- ing) (Berthoud and Morrison 2008). lived, possibly because of the development of tol- Pharmacological agents affecting feeding and erance (Fernstrom and Choi 2008). appetite. The complexity of neural mechanisms It is well known that typical (haloperidol) and underlying feeding behavior is reflected by the some atypical antipsychotic drugs (clozapine, number of pharmacological agents that are known olanzapine, and risperidone) increase appetite to affect this behavior. Commonly, these actions and body weight significantly. Conversely, are identified as side effects of treatments to other some atypical antipsychotic drugs, like pathological conditions and, subsequently, are used ziprasidone, may decrease appetite. Similarly, to control feeding behaviors. In some cases, these tricyclic antidepressants, monoamine oxidase medications are used to stimulate feeding in inhibitors, and some atypical antidepressants circumstances where patients are anorexic, but the also cause weight increases that range from mod- great majority of drugs aimed at modulating feed- erate to high (more than 10 %) over the treatment ing behavior are aimed at reducing caloric intake. It period. These medications include imipramine, is difficult, however, to identify a single neurotrans- phenelzine, mirtazapine, and trazodone. SSRIs mitter system as critical for food intake, as many are commonly associated with weight decreases have been implicated in the regulation of feeding early in treatment, but with body weight increases (Bray and Greenway 2007). after prolonged use. Treatment with the atypical Most appetite suppressants are drugs that antidepressant bupropion may result in decreased modify the release of monoamine and catechol- body weight (Jensen 2008). amine neurotransmitters in the brain. The most Central regulation of feeding and appetite. successful of these is sibutramine, a drug Feeding and appetite are both regulated by mul- approved by the US Food and Drug Administra- tiple brain regions (Berthoud and Morrison 2008; tion (FDA) for the treatment of obesity and Bray and Greenway 2007). The hypothalamus one that primarily inhibits the reuptake of 5-HT plays a predominant role in eliciting feeding and NE and, to a lesser extent, dopamine. responses as a means of achieving a homeostatic Sympathomimetics have also been approved by state. Early studies using hypothalamic lesions the FDA, including amphetamine, phentermine, emphasized the role of the mediobasal hypothal- benzphetamine, and phendimetrazine, although amus in mediating satiety responses and that of these are only prescribed for short-term use the lateral hypothalamus in mediating appetitive given their potential addictive properties. Finally, responses. More recently, however, it has become some antidepressant medications have anorectic clear that the hypothalamus contains a massive effects, including drugs such as fluoxetine, which peptidergic network that regulates food intake is a selective serotonin reuptake inhibitor (SSRI), and energy expenditure in response to hormonal and bupropion, a dopamine and norepinephrine and nutritional signals. One current idea is that reuptake inhibitor (Bray and Greenway 2007). the hypothalamic arcuate nucleus (ARC), There are a number of appetite suppressants a bilateral hypothalamic structure that surrounds that act through physiological mechanisms other the ventral portion of the third ventricle, plays Eating and Appetite 571 E a fundamental role in regulating feeding and signals from the mouth. Within the DVC, the energy homeostasis (Cone 2005). Indeed, the nucleus of the solitary tract (NTS) is the main ARC contains cells that are sensitive to all target for information ascending from the gut via peripheral signals that convey information about the vagus nerve and the enteric nervous system. energetic state and produce a number of peptides The NTS contains noradrenergic neurons that that influence food intake and appetite. A subset target and modulate the activity of hypothalamic of neurons in the ARC produce a-melanocyte- and limbic structures implicated in feeding, stimulating hormone (a-MSH), a cleaved product including the PVN and central nucleus of the of the proopiomelanocortin (POMC) precursor amygdala (CeA). The area postrema (AP), that decreases food intake and increases energy a second division of the DVC, lies outside of the E expenditure. A second subset of ARC neurons blood-brain barrier and is thus especially sensi- release two peptides that have a strong orexigenic tive to blood-borne nutritional signals, including effect: neuropeptide Y (NPY) and agouti-related those that are relayed by hormones like leptin, peptide (AGRP). Both a-MSH and AGRP com- insulin, cholecystokinin (CCK), and ghrelin, as pete for the same receptors (the melanocortin well as being sensitive to changes in circulating receptors 3 and 4, or MCR3 and MCR4) at target plasma levels of glucose. The AP transduces regions, with AGRP being a natural antagonist these signals and conveys them primarily to the and a-MSH being an agonist at these receptors NTS, where they are integrated with ascending (Cone 2005). Given these properties, the cells in visceral signals, but also directly onto the PVN, the ARC and the MCR3 and MCR4 receptors at where they may elicit feeding and autonomic their target brain sites are referred to as the responses. In addition to the regulation of feeding melanocortin system of energy regulation. In addi- responses, the brain stem plays a key role in the tion to NPY and melanocortin, peptides secreted generation of autonomic responses, being by other hypothalamic nuclei play an important involved in blood pressure regulation, respira- role in modulating feeding and appetite. For exam- tion, glucose release from the liver, vasoconstric- ple, cells in the lateral hypothalamus produce tion, lipolysis, and thermogenesis (Grill 2006). orexins/hypocretins or melanin-concentrating hor- Recent evidence has highlighted the role of the mone (MCH), both of which stimulate food intake midbrain in the regulation of feeding and appetite and appetitive responses. In contrast, cells in the (Volkow and Wise 2005). The midbrain contains paraventricular nucleus (PVN) of the hypothala- a number of cell groups implicated in brain func- mus release corticotrophic- and thyrotropin- tions underlying reward-seeking, learning and releasing hormone (CRH and TRH, respectively), memory processes, affective states, and the gen- which have an anorectic effect and stimulate eration of locomotor responses (Wise 2004). metabolic rate (Berthoud and Morrison 2008). Their role in the modulation of feeding responses Although the hypothalamus is important for is considered within the context of these pro- the regulation of energy balance, integration of cesses. Moreover, cells in these midbrain nuclei circulating metabolic signals occurs in several release neurotransmitters commonly implicated brain stem nuclei (Grill 2006). These nuclei are in the regulation of feeding and appetite. For intimately associated with autonomic responses example, DA cells of the ventral tegmentum that follow the activation of the stress axis by (VTA) and substantia nigra have been implicated psychogenic, metabolic, or immunological chal- in the modulation of food intake through their lenges. Within the brain stem, the three divisions projection to the striatum, prefrontal cortex, hip- of the dorsal vagal complex (DVC) play a key pocampus, and amygdala. Destruction of these role in integrating metabolic signals, with intero- pathways results in hypophagia similar to that ceptive afferent signals relaying information reported in animals with lateral hypothalamic from the digestive system via the vagus nerve (LH) lesions, and DA-deficient mice die of and information transmitted from cranial nerves starvation unless they are given exogenous that carry taste, texture, and sensory-motor L-3,4-dihydroxyphenylalanine (L-DOPA), a DA E 572 Eating Disorder: Anorexia Nervosa precursor (Palmiter 2007). In addition to ▶ Appetite Suppressants DA-related processes, serotonergic components ▶ Eating Disorders: Binge-Eating of the raphe nuclei have been implicated in the ▶ Endocannabinoids regulation of food intake. Indeed, there are 5-HT ▶ Hypocretins projections to hypothalamic and limbic centers ▶ Leptin involved in the regulation of food intake, and ▶ Melanin-Concentrating Hormone several lines of evidence demonstrate that 5-HT ▶ α-Melanocyte-Stimulating Hormone has an inhibitory effect on food intake, including clinical and experimental data on the anorectic effects of SSRIs. The effects of 5-HT on food References intake and metabolic function are mediated, at least in part, through the stimulation of POMC Berthoud HR, Morrison C (2008) The brain, appetite, and cells in the hypothalamic ARC, as well as through obesity. Annu Rev Psychol 59:55–92 Bray GA, Greenway FL (2007) Pharmacological treatment direct effects of 5-HT onto cells of the PVN of the overweight patient. Pharmacol Rev 59:151–184 (Zhou et al. 2005). Cone RD (2005) Anatomy and regulation of the central Circuits in the midbrain and brain stem are melanocortin system. Nat Neurosci 8:571–578 often viewed as either secondary or connected Fernstrom JD, Choi S (2008) The development of tolerance to drugs that suppress food intake. Pharmacol in series with the hypothalamus. In effect, their Ther 117:105–122 role in food intake regulation is that of an acces- Grill HJ (2006) Distributed neural control of energy bal- sory to the function of the hypothalamus. The fact ance: contributions from hindbrain and hypothalamus. that these centers are sensitive to the same periph- Obesity (Silver Spring) 14(Suppl 5):216S–221S Jensen GL (2008) Drug-induced hyperphagia: what can eral signals affecting the hypothalamus, however, we learn from psychiatric medications? J Parenter suggests that feeding regulation occurs via the Enteral Nutr 32:578–581 parallel activation of these circuits. In addition, Palmiter RD (2007) Is dopamine a physiologically rele- activation of brain stem or midbrain pathways vant mediator of feeding behavior? Trends Neurosci 30:375–381 may override regulatory signals from hypotha- Volkow ND, Wise RA (2005) How can drug addiction lamic homeostatic centers to modulate appetite. help us understand obesity? Nat Neurosci 8:555–560 The relative contribution of these brain path- Wise RA (2004) Dopamine, learning and motivation. Nat ways in mediating the effects of most drugs regu- Rev Neurosci 5:483–494 Zhou L, Williams T, Lachey JL, Kishi T, Cowley MA, lating feeding and appetite has not been fully Heisler LK (2005) Serotonergic pathways converge elucidated and continues to be a primary focus of upon central melanocortin systems to regulate energy investigation. Moreover, alterations in the activity balance. Peptides 26:1728–1732 of these circuits are thought to underlie eating disorders, such as anorexia nervosa, bulimia, binge eating disorder, and obesity. Undoubtedly, Eating Disorder: Anorexia Nervosa better knowledge of these brain circuits and the way in which drugs affect them will lead to the Christopher J. McDougle development of agents with fewer side effects Lurie Center for Autism and Department of involving these systems and improved effective- Psychiatry, MassGeneral Hospital for Children, ness of drugs targeted at them, ultimately leading to Lexington, MA, USA better appetite suppressants and orexigenic drugs. Nancy Lurie Marks Professor in the Field of Autism, Harvard Medical School, Boston, Cross-References MA, USA

▶ Anorexia Nervosa ▶ Antidepressants Synonyms ▶ Antipsychotic Drugs ▶ Appetite Stimulants Anorexia; Eating disorder Eating Disorder: Anorexia Nervosa 573 E

Definition Drug Treatment There is no officially approved medication for the Anorexia nervosa is a mental disorder character- treatment of anorexia nervosa. A variety of ized by a significantly low body weight (BMI agents have been examined with mostly discour- 17 kg/m2 or less in DSM-5), an intense fear of aging results with regard to facilitating weight gaining weight or of becoming fat, and gain or reducing associated cognitive and emo- a disturbance in the way in which one’s body tional symptoms such as body image distortion or weight or shape is experienced. Individuals with fear of weight gain. In addition, only a very few anorexia control their body weight by randomized controlled studies exist, usually with dieting – fasting, excessive exercise, or other inadequate sample sizes and high dropout rates. E weight-control behaviors such as self-induced Poor medication compliance seems to be vomiting or the misuse of laxatives, diuretics, or a particularly prominent problem in the treatment enemas. Women with this disorder develop of anorexia nervosa most likely due to the amenorrhea. patients’ ambivalence about treatment in general (Crow et al. 2009). Medication should not be used as the sole or primary treatment for anorexia Role of Pharmacotherapy nervosa (APA 2006; NICE 2004). Antidepres- sants and other psychiatric medications may be Diagnostic Categories used to treat associated symptoms of depressive, Anorexia nervosa primarily affects adolescent anxiety, obsessive-compulsive, and other comor- females and young women, and only about bid disorders; however, these symptoms may 5–10 % of people with the diagnosis are male. resolve with weight gain alone. When medication Two subtypes have been specified: is used to treat individuals with anorexia nervosa, the side effects of drug treatment (in particular, • Restricting Type: the person does not regularly cardiac side effects) should be carefully moni- engage in binge-eating or purging behavior tored. Bupropion is contraindicated in patients (i.e., self-induced vomiting, excessive exer- with eating disorders because of the increased cise, or the misuse of laxatives, diuretics, or seizure risk in these patients. Adverse reactions enemas). to tricyclic antidepressants and monoamine oxi- • Binge-Eating Type or Purging Type: the per- dase inhibitors (MAOIs) might be more pro- son regularly engages in binge-eating or purg- nounced in underweight individuals (Roerig ing behavior (i.e., self-induced vomiting or the et al. 2009). misuse of laxatives, diuretics, or enemas). Recently, second-generation antipsychotics, Anorexia nervosa is a serious and potentially particularly olanzapine, have been used in small life-threatening disorder with the highest stan- controlled trials. There is some evidence that dardized mortality rate among all psychiatric dis- olanzapine in a dose of 2.5–15 mg daily might orders, due to the chronic course, the associated increase the rate of weight gain and might reduce medical complications, and the mental comorbid- obsessive symptoms in patients with anorexia ity. The cumulative lifetime prevalence is esti- nervosa. If olanzapine is used, it is recommended mated to be 0.6 % in the general population that the patients be carefully monitored for extra- (Hudson et al. 2007) with an onset peak around pyramidal symptoms as well as for insulin resis- 15–19 years. Anorexia nervosa is frequently tance, abnormal lipid metabolism, and associated with other psychological symptoms prolongation of the QTc interval. including depression, anxiety, and obsessive- compulsive features. Therapy typically includes Conclusion nutritional rehabilitation and psychotherapeutic There is a very limited evidence base for the interventions; inpatient treatment is frequently pharmacological treatment of anorexia nervosa, required. and there is no convincing evidence to date of E 574 Eating Disorders: Animal Models efficacy for any drug treatment for anorexia Manual of Mental Disorders, 5th Edition nervosa in either the acute or chronic phase of (DSM-5): anorexia nervosa, bulimia nervosa, the disorder. and binge-eating disorder. These models attempt to mimic the altered patterns of food intake that Acknowledgment This is an update of the essay written comprise the core behavioral features of the by Martina de Zwaan for the first edition of this encyclo- human disorders. Some models also seek to pedia. mimic motivational, endocrine, or morphometric aspect of eating disorders. Cross-References Current Concepts and State of ▶ Antipsychotic Drugs Knowledge ▶ Eating and Appetite ▶ SSRIs and Related Compounds Applicability of Current Models to Human Eating Disorders References In addition to replicating the core symptoms defined in the DSM-5 (see Table 1), animal American Psychiatric Association (2006) Practice guide- models of eating disorders should address three lines for the treatment of patients with eating disorders, key elements: gender bias, comorbidity with 3rd edn. http://www.psych.org other psychiatric disorders, and adolescent Crow SJ et al (2009) What potential role is there for onset. Anorexia and bulimia affect three times medication treatment in anorexia nervosa? Int J Eat Disord 42:1–8 as many women as men (Hudson et al. 2007). Hudson JI et al (2007) The prevalence and correlates of The gender bias of binge-eating disorder is only eating disorders in the National Comorbidity Survey slightly less pronounced, with 1.75 times as many Replication. Biol Psychiatry 61(3):348–358 women as men affected during their lives. Given National Institute for Clinical Excellence (2004) Eating disorders. http://www.nice.org.uk this differential risk, animal models should incor- Roerig JL et al (2009) Pharmacological therapies for porate the study of females whenever possible. anorexia nervosa. In: Dancyger IF, Fornari VM (eds) Animal models should also address the high Evidence based treatments for eating disorders. Nova comorbidity with anxiety disorders, mood disor- Science, New York, pp 331–350 ders, impulse control disorders, and substance abuse. For example, anxiety- or depression- related variables might be conceived as experimental end points or as means to initiate Eating Disorders: Animal Models disordered eating behavior. Finally, because the median age of onset for all three disorders ranges Sarah Parylak1, Pietro Cottone2 and from the late teens to early twenties in humans, Eric P. Zorrilla1 models should prioritize the use of juvenile and 1The Scripps Research Institute, University of young adult animals. California San Diego, La Jolla, CA, USA An ideal animal model would possess face, 2Boston University School of Medicine, Boston, construct, and predictive validity, but eating dis- MA, USA orders present significant challenges to the development of such a model. Because the causes of anorexia, bulimia, and binge-eating Definition disorder in humans remain unclear, assessing the construct validity is difficult. The dearth of Animal models have been developed for the pharmacological agents effective for the treat- study of each of the three most common eating ment of eating disorders also hinders assessment disorders listed in the Diagnostic and Statistical of predictive validity. No FDA-approved Eating Disorders: Animal Models 575 E

Eating Disorders: Animal Models, Table 1 Summary Models of Anorexia Nervosa of eating disorder diagnostic criteria An effective model of anorexia nervosa should Anorexia Restriction of energy intake relative to mimic the core symptoms of a voluntarily low nervosa requirements, leading to body and reduced food intake in females. Hyper- a significantly low body mass index activity with high levels of energy expenditure (BMI) Intense fear of weight gain (e.g., compulsive exercise) and amenorrhea, Disturbed perception of body shape or though not part of the core diagnostic criteria, denial of seriously low body weight are also extremely common. Efforts to recreate Bulimia Recurrent episodes of binge eating. these symptoms have included both genetic and nervosa The binge-eating episodes can occur environmental models. As mentioned previously, E when not feeling physically hungry animal models are not suited to address the and can be associated with increased eating rate, feeling uncomfortably intense fear of weight gain and distorted body full, embarrassment, and guiltiness image seen in anorexics. Recurrent compensatory behaviors to prevent weight gain (e.g., vomiting, The anx/anx Mouse laxative use) The most commonly studied genetic model is the Binging and compensatory behaviors occur at least twice weekly for anx/anx mouse. Additional, less widely studied 3 months genetic models of anorexia include the contactin- Self-evaluation excessively deficient mouse and the dopamine-deficient influenced by body shape mouse; others too have studied the hypophagic Does not meet criteria for anorexia phenotypes of knockout mice, including the nervosa MCH, Crh2, and M3 receptor null mutants, as Binge-eating Recurrent episodes of binge eating disorder which occur within a discrete period modeling aspects of the anorexia nervosa syn- of time (e.g., within any 2-h period) drome. The anx mutation, which arose spontane- and are accompanied by lack of ously at Jackson Laboratories, is an autosomal control over eating recessive trait that results in a dangerously low Feelings of distress about binge eating food intake. Anx/anx mice are emaciated and The binge eating occurs at least once exhibit motor symptoms including body tremors, a week for 3 months hyperactivity, headweaving, and uncoordinated Does not meet criteria for anorexia or bulimia nervosa gait. The anx mutation is lethal within 3–4 weeks of birth depending on the genetic background. The gene product of anx is treatment currently exists for the treatment unknown, but the mutation has been localized to of anorexia or binge-eating disorder, and fluox- a 0.2-cM interval corresponding to 1.28 Mbp on etine is the only medication currently approved mouse chromosome 2 (Johansen et al. 2003). The by the FDA for the treatment of bulimia. Due to model is valuable due to its ability to reduce food these issues, animal models have sought to intake without forced starvation or use of achieve face validity. Animal models are further a pharmacological agent as an appetite suppres- limited, however, by their inability to mimic sant. It has been simultaneously criticized, how- certain psychological or social components ever, because appetite itself, if not hunger, of eating disorders. Despite these limitations, appears intact in human anorexics. Moreover, animal models can serve as powerful hypothesis based on gene expression profiling, the anx/anx generators for further study in humans of mouse has been recently suggested to model the biological underpinnings or consequences cachexia, rather than anorexia nervosa or of eating disorders. Current models have starvation. focusedoverwhelminglyonrodentsandcanbe The anx/anx mouse shows several neurobio- broadly divided into anorexia-like and binge- logical abnormalities that may underlie its phe- like paradigms. notype. Two cell populations in the arcuate E 576 Eating Disorders: Animal Models nucleus of the hypothalamus exert opposing As in the anx/anx mouse, several neurochem- influences on food intake in normal individuals. ical abnormalities have been observed in the One population produces the orexigenic signals hypothalamus following activity-based anorexia. neuropeptide Y (NPY) and agouti-related protein Rodents subjected to activity-based anorexia (AgRP). A second population that produces show increased NPY and AgRP mRNA in the proopiomelanocortin (POMC) and cocaine- and arcuate nucleus after 3 days of hyperactivity amphetamine-regulated transcript (CART) yields combined with lower levels of POMC and anorexigenic signals. In anx/anx mice, NPY and CART mRNA. Leptin levels drop rapidly AgRP accumulate in the cell body but are during activity-based anorexia, and leptin admin- reduced in axon terminals. Decreased NPY istration can rescue low body weights. Hypotha- receptor mRNA levels have also been seen as lamic levels of b-endorphin are elevated when well as possible compensatory responses to star- animals on this paradigm lose 25 % of their vation, including reduced POMC and CART normal body weight, and serotonin levels are levels and low serum leptin levels. Serotonergic elevated in the medial basal hypothalamus hyperinnervation of several forebrain structures, (Hillebrand et al. 2008). In this respect, activity- including the arcuate nucleus, has also been based anorexia may parallel the human condition, observed. This hyperinnervation may be behav- as reduced CSF levels of the serotonin metabolite iorally relevant given the anorectic influence of 5HTIAA are observed in anorexic patients. Per- serotonin. Outside the hypothalamus, the anx/anx haps lending some predictive validity, the atypi- mouse also exhibits reduced striatal dopamine cal antipsychotic olanzapine appears to attenuate levels and reduced sensitivity to dopamine’s hyperactivity in both activity-based anorexia and action to reduce Na+/K+-ATPase activity. human subjects. Further work is necessary to characterize fully any causal relationship Activity-Based Anorexia between the neurochemical changes and the The most widespread nongenetic model of hyperactivity and starvation seen in the model. anorexia nervosa is activity-based anorexia, also known as starvation-induced hyperactivity. Models of Bulimia Nervosa and Binge-Eating Rodents receiving time-limited daily access to Disorder food will increase intake during that time to main- Both bulimia nervosa and binge-eating disorder tain a stable body weight. In the activity-based are characterized by recurrent episodes of binge anorexia model, this compensatory feeding behav- eating – consuming more within a given time ior is disrupted by providing access to a running than a normal individual would eat under the wheel. Details of food and wheel availability vary same circumstances – and animal models have between investigative groups, but wheel access sought to replicate this core symptom. Several typically exceeds food access in duration. Under factors believed to contribute to or precipitate these conditions, animals dramatically reduce food binges in humans have been used to elicit binge intake while increasing wheel running, such that eating in rodents, including food restriction energy expenditure surpasses energy intake. Body followed by free feeding, intermittent access to weights decline, and animals will eventually die highly palatable food, and stress. As in anorexia without experimenter intervention. This paradigm nervosa, animal models cannot mimic several thus jointly models the hyperactivity and voluntary psychological features of the disorder, including decrease in food intake seen in human anorexics. preoccupation with body image. Female rats also escalate their running more rapidly than males and stop estrous cycling. Unlike Sham Feeding human anorexia, however, body weights recover Bulimia can be differentiated from binge-eating under activity-based anorexia conditions if food disorder by the presence of compensatory behav- access is increased or if palatable, high-fat food is iors including purging, laxative abuse, fasting, or provided. compulsive exercise. Rodents lack a vomiting Eating Disorders: Animal Models 577 E reflex, but sham-feeding models have been used when fasting (Avena et al. 2008), reduced hypo- to mimic purging in rodents. In sham feeding, thalamic dopamine, and reduced serotonin and a gastric fistula is used to drain the recently dopamine in the medial prefrontal cortex ingested meal from the stomach before it reaches (Chandler-Laney et al. 2007). the intestine. The animal thus experiences gusta- tory feedback while consuming the meal, but Palatable Food receives minimal postingestive satiety signals Palatable foods high in sugar or fat can promote from the digestive tract. Sham-fed animals binge-like intake with little or no food restriction. increase their meal size and consume meals It has been proposed that limiting access to these more rapidly, analogous to human bulimics. “forbidden foods” contributes to their E A limitation of the sham-feeding model is that overconsumption during episodes of human compensatory behaviors in humans are voluntary binge eating or when dieters “cheat” on a diet. and thought to occur despite homeostatic regula- Several animal models alternate between access tion, whereas sham feeding is experimentally to a standard chow diet and access to a preferred induced and results from homeostatic processes. diet to mimic this cyclical pattern of restraint and relapse. As access to a palatable food is decreased Restriction and Refeeding Cycles in rodents, the rate at which it is consumed when Binge-like behavior can be elicited in rodents by it becomes available again increases. Corwin and restricting food access for an extended period and Wojnicki (2006) have developed a model using then returning the animals to ad libitum food a pure fat (vegetable shortening), provided for access for a refeeding period. This cycle of only 1–2 h three times per week while chow restriction and refeeding may be repeated numer- remains available ad lib at all times. After approx- ous times. Animals typically increase their intake imately 4 weeks on this schedule, intake of the during the refeeding period relative to animals pure fat increases dramatically, eventually com- without a history of restriction, a phenomenon prising approximately 70 % of normal total daily known as rebound hyperphagia. A normal indi- intake in ad lib chow-fed rats. Fat intake under vidual would be expected to increase consump- these limited-access conditions is unaffected by tion after forced restriction; thus, this the administration of galanin or enterostatin, two hyperphagia is not a perfect analog of human peptides involved in regulating fat consumption, binges, which frequently occur even in the but can be reduced with the GABAB agonist absence of hunger. Additional factors such as baclofen. Baclofen does not alter the intake of palatable foods and stress can be added, however, chow, suggesting that the binge-like intake of to increase the validity of the model. Rats allowed the fat is driven by some property of the high-fat to refeed on palatable food, such as a high-fat diet, perhaps its palatability. cookie diet or sucrose, have greater hyperphagia Further restricting palatable food access can than those allowed to refeed on chow. Such pal- produce binge-like behavior more rapidly. atable foods share greater similarity to the high- Cottone et al. (2008) have developed a model of fat, high-sugar foods typically consumed during binge eating where a daily 2-h period of food human binges. Rats with a history of restriction deprivation is followed by access to a high- and refeeding on palatable food also show sucrose diet for only 10 min. Chow is available depressive-like and anxiety-like symptoms, ad lib at all other times. On this schedule, rats suggesting that such models might be useful for rapidly increase their intake of the high-sucrose studying the high comorbidity of binge eating diet beginning on the second day of exposure, with mood and anxiety disorders. Alterations in eventually consuming 40–50 % of total daily monoamine function in these animals have also intake during the 10-min limited-access session. been observed. Changes include reduced extra- Binge magnitude is reduced by the administration cellular dopamine accompanied by increased of the mu- and kappa-opioid antagonist acetylcholine in the nucleus accumbens shell nalmefene. E 578 Eating Disorders: Animal Models

Anxiety appears to be increased on both the to refeed in cages that severely restrict move- 2-h and 10-min binge schedules. Heightened anx- ment (Inoue et al. 1998). This cycle of restric- iety may reﬂect a dysphoric state (affective state) tion, stress, and binging on a rewarding stimulus induced by withdrawal from the preferred diet. bears a remarkable similarity to drug addiction, Rats alternating between 5 days of access to stan- and it has been suggested that binge eating dard chow and 2 days of access to a palatable should be examined from the same perspective high-sucrose diet show an increase in as substance abuse disorders. As with addiction, anxiety-like behavior only when tested on days humans with bulimia or binge-eating disorder when the palatable food is unavailable. report a loss of control during a binge despite Benzodiazepines, known for their potent anxi- feelings of shame or guilt. Uncovering further olytic effects, increase palatable food consump- similarities in the mechanisms of substance use tion in nondeprived animals and humans. These and binge eating may help reﬁne existing models orexigenic effects are dissociable from effects on of both categories. anxiety, as not all benzodiazepine partial agonists that are anxiolytic also stimulate food intake. Benzodiazepines may instead act to enhance Cross-References hedonic responses to palatable foods. They enhance preferences for sweet or salty tastes and ▶ Abstinence increase motivation to obtain a food reinforcer in ▶ Addictive Disorder: Animal Models rats trained on a progressive ratio schedule. In ▶ Animal Models for Psychiatric States contrast, benzodiazepine inverse agonists attenu- ▶ Appetite Stimulants ate taste preferences and reduce palatable food ▶ Appetite Suppressants intake by reducing the length of feeding bouts ▶ Craving (Cooper 2005). ▶ Eating and Appetite ▶ Eating Disorder: Anorexia Nervosa Stress ▶ Energy Balance Acute stress typically reduces food intake in rodents, but Boggiano et al. (2005) have developed a model that combines restriction- refeeding cycles with palatable food and stress References to cause binge-like behavior. In this model, rats are placed on food restriction (67 % of normal Avena NM, Rada P, Hoebel BG (2008) Evidence for sugar intake) and are allowed to refeed on chow or addiction: behavioral and neurochemical effects of palatablefoodadlibandthenareexposedto intermittent, excessive sugar intake. Neurosci Biobehav Rev 31:20–39 a footshock stressor. Rats placed on this restric- Boggiano MM, Chandler PC, Viana JB, Oswald KD, tion/stress schedule increase their intake of pal- Maldonado CR, Wauford PK (2005) Combined atable food after the footshock relative to rats dieting and stress evoke exaggerated responses to opi- exposed to either restriction or stress alone, indi- oids in binge-eating rats. Behav Neurosci 119:1207–1214 cating that a synergistic effect of restriction and Chandler-Laney PC, Castaneda E, Pritchett CE, Smith stress drives the binge. Binges can be attenuated ML, Giddings M, Artiga AI, Boggiano MM with naloxone (opioid antagonist) treatment, (2007) A history of caloric restriction induces neuro- suggesting that the drive to consume the palat- chemical and behavioral changes in rats consistent with models of depression. Pharmacol Biochem able food is related to reward seeking. If chow Behav 87:104–114 alone is available during the refeeding phase, Cooper SJ (2005) Palatability-dependent appetite and ben- binge-like behavior is absent. Other stressors zodiazepines: new directions from the pharmacology can also precipitate a binge. Rebound chow of GABA(A) receptor subtypes. Appetite 44:133–150 Corwin RL, Wojnicki FH (2006) Binge eating in rats with hyperphagia is enhanced if rats with a history limited access to vegetable shortening. Curr Protoc of 2-h time-limited daily food access are allowed Neurosci 9(9):23B Eating Disorders: Binge Eating 579 E

Cottone P, Sabino V, Steardo L, Zorrilla EP (2008) indicators of loss of control and distress, but not Opioid-dependent anticipatory negative contrast and with the inappropriate compensatory weight loss binge-like eating in rats with limited access to highly preferred food. Neuropsychopharmacology behaviors of BN. Of note, binge eating may also 33:524–535 occur in anorexia nervosa (AN), but is not Hillebrand JJ, Kas MJ, van Elburg AA, Hoek HW, Adan required for its diagnosis. RA (2008) Leptin’s effect on hyperactivity: potential downstream effector mechanisms. Physiol Behav 94:689–695 Hudson JI, Hiripi E, Pope HG Jr, Kessler RC (2007) The Role of Pharmacotherapy prevalence and correlates of eating disorders in the national comorbidity survey replication. Biol Psychi- Specialized psychotherapies, in particular cogni- atry 61:348–358 E Inoue K, Kiriike N, Okuno M, Fujisaki Y, Kurioka M, tive behavior therapy [CBT] and interpersonal Iwasaki S, Yamagami S (1998) Prefrontal and striatal therapy [IPT], and self-help strategies are effec- dopamine metabolism during enhanced rebound tive for reducing binge eating in BN and BED, hyperphagia induced by space restriction-a rat model but not all patients respond adequately. More- of binge eating. Biol Psychiatry 44:1329–1336 Johansen JE, Fetissov S, Fischer H, Arvidsson S, over, these treatments are generally not effective Hokfelt T, Schalling M (2003) Approaches to anorexia for some of the common comorbidities of binge in rodents: focus on the anx/anx mouse. Eur eating, such as obesity. Increasing evidence indi- J Pharmacol 480:171–176 cates that pharmacotherapy may play an important role in treating patients with BN or BED, including in patients who respond inadequately to psychotherapy, patients with comorbid medi- Eating Disorders: Binge Eating cal or psychiatric disorders, and those with chronic or intractable illness (McElroy Susan L. McElroy1,2 and Anna I. Guerdjikova1,2 et al. 2012a). Only one drug, however, has regu- 1Research Institute, Lindner Center of HOPE, latory approval for the treatment of binge eating, Mason, OH, USA that being fluoxetine for BN. No drug is yet 2Department of Psychiatry & Behavioral approved for the treatment of BED, binge Neuroscience, University of Cincinnati College eating associated with AN, or binge-eating of Medicine, Cincinnati, OH, USA behavior in general. Bupropion is specifically contraindicated in BN and AN because of the potential for increase in seizures. Synonyms Medication classes receiving the most study in binge eating are antidepressants, antiepileptics, Compulsive overeating; Loss of control eating and antiobesity drugs. Medications for attention-deficit hyperactivity disorder (ADHD),

anti-addiction (or anti-craving) agents, 5HT3 Definition antagonists, hormonal agents, and lithium have received less empirical attention. Binge eating is the consumption of an abnormally large amount of food in a discrete period of time accompanied by a sense of loss of control. Binge Antidepressants eating is a core defining feature of two eating disorders: bulimia nervosa (BN) and binge-eating The most extensively studied drug class in BN disorder (BED). BN is further defined by inap- and BED, a broad range of antidepressants reduce propriate compensatory weight loss behaviors binge-eating behavior in BN and BED over the (e.g., self-induced vomiting) and excessive con- short term (Bacaltchuk and Hay 2003; FBNCSG cern for shape and weight. By contrast, for BED, 1992; Guerdjikova et al. 2012). Antidepressants binge eating must be associated with other are also effective for reducing purging behavior E 580 Eating Disorders: Binge Eating in BN and depressive symptoms in both BN and combination therapy RCTs of antidepressants in BED. Bupropion, unlike selective serotonin reup- BED had contrasting results. take inhibitors (SSRIs) or tricyclic antidepressants (TCAs), may have modest but clinically significant weight loss effects in BED, but is Antiepileptic Drugs contraindicated in BN because of a potential increased risk of seizures (White and Considerable double-blind, placebo-controlled Grilo 2013). No randomized, placebo-controlled data show that topiramate is effective for the trials (RCTs) comparing antidepressants with dif- binge eating of BN and BED. Topiramate is ferent mechanisms of action have been conducted also effective for correlates of binge eating, in BN or BED, but meta-analyses suggest differ- such as purging in BN, obsessive-compulsive ent classes of antidepressants may be comparably binge-eating features in BED, and for weight effective for reducing binge eating in BN loss in BED with co-occurring obesity. Doses (Bacaltchuk and Hay 2003). studied in BN (25–400 mg/day) have been gen- In the largest study of an antidepressant in BN erally lower than those in BED (25–600 mg/day). (N = 387), fluoxetine 60 mg/day was superior to One RCT showed topiramate may enhance the placebo for reducing binge eating and vomiting effectiveness of CBT in BED, for both binge episodes, while 20 mg/day was shown to have an eating and weight loss, while an open-label intermediate effect (FBNCSG 1992). There are study found topiramate’s anti-binge-eating and no published dose response studies of antidepres- weight loss effects in BED may persist for up to sants in BED. The serotonin-norepinephrine 1 year (though drug discontinuation rates were reuptake inhibitor (SNRI) duloxetine may high, in part due to adverse events). Commonly decrease binge eating, body weight, and global reported side effects are paresthesia, dry measures of psychopathology in BED when mouth, headache, somnolence, gastrointestinal it co-occurs with a depressive disorder disturbance, taste perversion, and cognitive (Guerdjikova et al. 2012). impairment. Two relapse-prevention RCTs suggest fluoxe- Topiramate has also been reported to reduce tine and fluvoxamine may reduce binge eating in BN or BED symptoms in patients with treatment- BN patients over extended periods of time resistant illness, including those with comorbid (12–52 weeks), but were limited by high attrition depressive or bipolar disorders, traumatic brain rates (Romano et al. 2002). Comparable relapse- injury or epilepsy, those receiving the drug prevention RCTs of antidepressant monotherapy adjunctively with antidepressants and/or mood in BED have not yet been conducted, but prelim- stabilizers, and those with binge-eating symp- inary data has suggested that some patients with toms after bariatric surgery. On the other hand, BED who initially respond to SSRIs with there are reports of topiramate misuse in eating decreased binge eating and weight loss may disorder patients. maintain these benefits for up to 6 months with The only other AED shown to reduce binge continuation of the SSRI. eating in a RCT is zonisamide. In that small Studies comparing antidepressants with psy- study, zonisamide reduced binge eating, chological treatments or their combination for obsessive-compulsive binge-eating features, and reducing symptoms in BN suggest that the com- body weight in BED patients with co-occurring bination of an antidepressant plus psychotherapy obesity, but was associated with a high dropout may be superior to psychotherapy treatment rate. There are negative (or failed) RCTs of car- alone, but that dropout rates are higher for com- bamazepine in BN and lamotrigine in BED. Con- bination therapy compared with psychotherapy trolled data on phenytoin in binge-eating treatment alone (Bacaltchuk et al. 2001). Fluox- populations are limited and mixed. In patients etine may be efficacious for BN after psychother- with comorbid bipolar disorder, valproate has apy has failed to work. The few controlled been reported to improve binge-purge symptoms Eating Disorders: Binge Eating 581 E in BN, but to worsen binge eating and enhance flexible-dose RCT of lisdexamfetamine in BED weight gain in BED. (NCT01090713) are ongoing.

Antiobesity Agents Anti-addiction (or Anti-craving) Drugs

Although D-fenfluramine may reduce binge eat- Small placebo-controlled RCTs of orally admin- ing in BN and BED and sibutramine reduces istered opioid antagonists (naltrexone and the binge eating and body weight in BED, both com- investigational agent ALKS 33), at doses effec- pounds have been removed from the worldwide tive for substance dependence, were largely neg- E market for safety concerns. Similarly, the ative for reducing binge eating in BN and BED endocannabinoid receptor antagonist rimonabant (McElroy et al. 2013). Other studies, however, may reduce weight and binge-eating behavior in have suggested that naltrexone administered in obese patients, but is no longer available. Orlistat supratherapeutic doses (200–400 mg/day), or in has not been evaluated in BN, but has been shown conjunction with an antidepressant, may decrease to enhance weight loss and possibly reduce binge binge eating, including in patients with eating in BED co-occurring with obesity, includ- treatment-resistant illness or comorbid diabetes. ing when given with guided self-help delivered Naltrexone in combination with bupropion CBT. Orlistat has also been shown to reduce (Contrave) is associated with more weight loss waist circumference, hip circumference, total in obesity than either drug alone and has been percentage body fat, total cholesterol level, shown to reduce binge-eating behavior in patients diastolic blood pressure, and insulin level in with major depressive disorder and obesity. Pre- obese patients with binge eating. However, liminary results from an RCT suggest intranasal orlistat misuse has been reported in patients naloxone spray may reduce time spent binge eat- with BN and BED. ing in BED. Small RCTs suggest the anti-craving The combination of bupropion and naltrexone drugs acamprosate and baclofen may reduce extended release (Contrave) is under evaluation binge-eating behavior, but further study is needed for obesity and has been shown to decrease binge- (Corwin et al 2012). eating symptoms in overweight or obese women with depression. The new antiobesity medications lorcaserin (Belviq) and the combination of Other Agents phentermine and topiramate extended release (Qysmia) have not yet been evaluated in binge- There are small negative RCTs of spironolactone, eating populations. flutamide, and lithium for binge eating in BN. However, case reports have described the successful treatment with lithium of patients Drugs for ADHD with BN or BED and comorbid bipolar disorder. A small RCT of the dietary supplement chro- Single small RCTs suggest atomoxetine and intra- mium picolinate showed this agent significantly venous methylamphetamine may reduce binge reduced fasting glucose in BED patients. eating in BED and BN, respectively. Preliminary Another small RCT showed ondansetron, self- results from a recently completed fixed-dose phase administered in 4 mg capsules up to 6 per day II study of lisdexamfetamine in 270 patients with upon the urge to binge or vomit, was associated moderate-to-severe BED found the drug, at with a significantly greater decrease in binge/ doses of 50 and 70 mg/day but not 30 mg/day, vomit frequencies in patients with severe was superior to placebo for reducing binge eating BN. Reports of QT interval prolongation with (McElroy et al. 2012b). Two large phase III studies ondansetron prompted the FDA to advise that (NCT01718483 and NCT01718509) and a smaller ondansetron not be used in patients with E 582 Eating Disorders: Binge Eating congenital long QT syndrome and that ECG mon- BN should be fluoxetine (or another SSRI); for itoring be conducted when using the drug in cer- BED, topiramate, an antidepressant, or lisdexam- tain clinical situations, including in patients with fetamine should be considered. Though electrolyte abnormalities. bupropion is contraindicated for BN, it may be The glutamate modulating agent memantine useful in BED, in part due to its weight and the sodium salt of g hydroxybutyrate, sodium loss effects. Zonisamide may be considered in oxybate, have been reported to reduce binge eat- patients unable to tolerate topiramate, especially ing in patients with BED in open trials. Placebo- if they responded to the drug. Some patients with controlled RCTs of the wakefulness-promoting BN or BED may require combination pharmaco- agent armodafinil (NCT01010789) and the therapy for optimal results. glucagon-like peptide (GLP-1) analog liraglutide Although empirical data are sparse, antidepres- (used for the treatment of type 2 diabetes) sants may be helpful for BN or BED patients with (NCT01739049) in BED are ongoing. a depressive or anxiety disorder, topiramate or There are no published RCTs of antipsy- zonisamide for those with comorbid chotics in BN or BED. Rather, second-generation obesity and/or an obesity-related complication, antipsychotics have been reported to induce or atomoxetine or stimulants for those with comorbid exacerbate binge eating in patients with eating ADHD, and anti-addiction or anti-craving drugs disorders, as well as in patients with psychotic for those with co-occurring substance use disor- disorders. ders. No empirical data are available for treating BN or BED patients with bipolar disorder. In bipolar patients with binge eating along with obesity or Summary fear of weight gain from taking a mood stabilizer, agents effective in mania or bipolar depression that Although the evidence base is small, growing have minimal effects on weight may be consid- data indicate pharmacotherapy may be helpful ered, such as the second-generation antipsychotics for reducing binge eating in some patients with aripiprazole, lurasidone, or ziprasidone for pre- BN or BED. Antidepressants, especially selective dominantly manic presentations and lamotrigine serotonin reuptake inhibitors (SSRIs), are mod- or lurasidone for predominantly depressive pre- estly effective for reducing binge eating over the sentations. For patients with BN or BED who short term in BN and BED. SSRIs may be mod- have mood-stabilizing responses but continue to estly effective in BN over the long term. binge eat, augmentation with topiramate, stimu- Topiramate is effective for binge eating in BED lants, or antidepressants may be considered. Elec- and BN, but side effects may limit its usefulness. trolyte disturbances must be monitored for in Single RCTs suggest ondansetron may be effec- patients with purging behavior who are treated tive for reducing binge eating in BN and that with lithium. zonisamide, atomoxetine, and lisdexamfetamine In sum, pharmacotherapy has an important may decrease binge eating in BED. It is not yet role in the management of BN and BED, includ- known whether the binge eating of BN and BED ing in patients inadequately responsive to psy- responds similarly to pharmacotherapy. chotherapy, patients with comorbid psychiatric Pharmacotherapy should be considered or medical disorders, and those with chronic or a therapeutic option for most BN and BED intractable illness. However, the available patients, including when binge eating has pharmacotherapeutic armamentarium for both responded inadequately to psychotherapy, conditions and its supporting evidence base psychotherapy is unavailable, the patient is far from adequate. Further study is needed prefers pharmacotherapy to psychotherapy, and to clarify which specific agents, and combina- pharmacotherapy-responsive comorbid conditions of agents, might be most useful for which tions are present. First-line pharmacotherapy for patient subgroups, as well as to delineate Echopraxia 583 E the larger role of pharmacotherapy in relationship to other treatments. Echolalia

Definition Cross-References The involuntary repetition, usually immediately, ▶ Antidepressants of words, phrases, or other vocalizations made by ▶ Topiramate another person; usually seen in psychotic and ▶ Opioid Antagonist autism spectrum disorders (e.g., autism). E References

Bacaltchuk J, Hay P (2003) Antidepressants versus placebo for people with bulimia nervosa. Cochrane Echo-Planar Imaging Database Syst Rev 4, CD003391 Bacaltchuk J, Hay P, Trefiglio R (2001) Antidepressants Synonyms versus psychological treatments and their combination for bulimia nervosa. Cochrane Database Syst Rev 4, CD003385 Gradient-echo EPI; Spin-echo EPI Corwin RL, Boan J, Peters KF, Ulbrecht JS (2012) Baclo- fen reduces binge eating in a double-blind, placebo- controlled, crossover study. Behav Pharmacol Definition 23(5–6):616–625 FBNCSG (1992) Fluoxetine in the treatment of bulimia nervosa. A multicenter, placebo-controlled, double- Echo-planar imaging (EPI) is a ▶ magnetic reso- blind trial. Arch Gen Psychiatry 49:139–147 nance imaging (MRI) technique that permits the Guerdjikova AI, McElroy SL, Winstanley EL, Nelson EB, rapid collection of entire two-dimensional MR Mori N, McCoy J et al (2012) Duloxetine in the treatment of binge eating disorder with depressive disor- images (slices) in only a fraction of a second ders: a placebo-controlled trial. Int J Eat Disord (40–100 ms). It has been fundamental to the 45:281–289 development of blood-oxygen-level-dependent McElroy SL, Guerdjikova AI, Mori N, O’Melia AM (BOLD) fMRI. (2012a) Current pharmacotherapy options for bulimia nervosa and binge eating disorder. Expert Opin Pharmacother 13(14):2015–2026 McElroy SL, Mitchell J, Wilfley D, Gasior M, Ferreira- Cross-References Cornwell MC, Gao J et al (2012b) Efficacy and safety of lisdexamfetamine dimesylate in treatment of adults ▶ with binge eating disorder. A randomized, double- Magnetic Resonance Imaging (Functional) blind placebo-controlled trial. Neuropsycho pharmacology 38(51):5333–5334 McElroy SL, Guerdjikova AI, Blom TJ, Crow SJ, Memisoglu A, Silverman BL et al (2013) A placebo- controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder. Int Echopraxia J Eat Disord 46:239–245 Romano SJ, Halmi KA, Sarkar NP, Koke SC, Lee JS Definition (2002) A placebo-controlled study of fluoxetine in continued treatment of bulimia nervosa after successful acute fluoxetine treatment. Am J Psychiatry The involuntary imitation or mirroring, usually 159(1):96–102 immediately, of the movements made by another White MA, Grilo CM (2013) Bupropion for overweight person; usually seen in Tourette syndrome and in women with binge-eating disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychia- psychotic and autism spectrum disorders (e.g., try 74(4):400–406 autism). E 584 Ecogenetics

effects that did not necessarily reach the Ecogenetics extremes of a percentage scale. For example, in drug discrimination experiments using

Synonyms graded scales, the ED50 value is often deﬁned as the dose of the drug that produces a mean of Ecological genetics 50 % drug-appropriate responding, as estimated from dose-response data by an appropriate sta-

tistical method. The ED50 is a valuable index Definition for comparing potency in a series of related substances. Ecogenetics is a branch of genetics that studies how the genetic makeup affects the way organisms respond to all kinds of environmental sub- Cross-References stances. This ﬁeld deals with the genetic basis of environmental toxicity to develop methods for ▶ Drug Discrimination the detection, prevention, and control of envi- ronmentally related disease. According to the environmental agents involved, one may distinguish infection ecogenetics, nutritional Effect Inversion ecogenetics, physical ecogenetics, and chemical ecogenetics. Synonyms

Opposite effect Cross-References

▶ Pharmacogenetics Definition ▶ Pharmacogenomics Inversion (reversal) in the nature of the effect(s) exerted by a biologically active substance, such that its effect is opposite to that normally seen. ED50 This phenomenon may be triggered, on the one hand, by the intake (or administration) of a dose Definition much higher than the one capable of exerting the usual effect. On the other hand, effect inver-

The ED50 is a commonly used abbreviation that sion may emerge as a consequence of the denotes the effective dose of a drug needed to prolonged consumption (or administration) of produce a particular response in 50 % of a pop- low to moderate doses of an active substance. ulation of test samples. It is a quantitative mea- In the latter case, effect inversion is distinct sure of the potency of a drug; the smaller the from tolerance and leads to the manifestation

ED50 value, the more potent is the substance in of effects that are opposite to those exerted by the test system used. The original use of the the substance upon its single intake (or acute term, as deﬁned above, related to drug effects administration). of an all-or-none (quantal) nature, and it was assumed that the full range of effect frequencies from 0 % to 100 % actually occurred. Subse- quently the term was adapted to a wider range Cross-References of test situations including those where quantitative (graded) data were obtained for drug ▶ Caffeine Efficacy 585 E

conditions. They are routinely short term (e.g., Effect Size 4–12 weeks), with strict inclusion/exclusion criteria and placebo and/or comparator drug con- Synonyms trol groups. Such trials are integral to regulatory approval in drug development. In contrast, effec- Standardized mean difference tiveness trials evaluate the performance of an agent in the “real world” of actual clinical practice, unencumbered by the same restrictive Definition criteria and required control groups. Efficacy does not ensure effectiveness, as has E Effect size (ES) is a term given to a family of been demonstrated recently following wide- indices that measure the magnitude of a treatment spread adoption of the atypical antipsychotics. effect. Unlike significance tests, effect size is inde- Numerous efficacy trials with individual atypical pendent of sample size. Effect sizes are used when antipsychotic agents demonstrated their treatment effects are defined over a continuous superiority when compared to placebo, as measure. In clinical trials, for a given treatment, well as to a typical (conventional) effect size is usually defined as the mean improve- antipsychotic. However, subsequent effective- ment over the course of a trial divided by the ness studies tempered these findings; in the standard deviation for the treatment group. Based more naturalistic environment of actual clinical on convention, a small effect size is considered practice, the atypical antipsychotics failed to dis- less than 0.3, medium effect size 0.3-0.7, and tinguish themselves from conventional agents in a large effect size greater than 0.7. the manner reported in efficacy trials. These findings highlight the need for both efficacy and effectiveness studies in drug evalu- Effectiveness ation. Proven efficacy is necessary, but not sufficient, to guarantee effectiveness in actual clinical Synonyms practice.

Pragmatic outcome; Usefulness Cross-References

Definition ▶ Second- and Third-Generation Antipsychotics

The beneﬁcial effect of a medicinal product seen in everyday clinical practice, in relatively unselected patients who may have psychiatric or medical Efficacy comorbidities, who may be taking concomitant medication, whose adherence with medication is Synonyms unsupervised and where the outcome is useful to the patient in terms of quality of life. Clinical outcome; Therapeutic beneﬁt

Effectiveness Studies Definition

Definition In pharmacological investigations, efficacy is the property of an agonist drug at its receptor that Efficacy trials in psychopharmacology examine reflects its ability to produce a response. Drugs the performance of an agent under “ideal” that act at the same receptor can vary in their E 586 Effort Cost efficacies. Efficacy depends on whether a drug acts as a full, partial, or inverse agonist. Pure Elasticity antagonist drugs occupy receptors but have no efficacy. Synonyms In clinical situations, efficacy refers to the beneficial effect of a medicinal product under Adjustability; Flexibility; Malleability; Plastic- ideal conditions – usually phase 2 or 3 clinical ity; Pliancy trials conducted at least partially in a hospital setting and involving a selected subsample of the population for which the medicine will eventu- Definition ally be indicated and where outcome is typically measured by symptom ratings. Elasticity is the degree to which a change in price or income changes the demand for a commodity.

Cross-References Effort Cost ▶ Behavioral Economics Definition

The subjective appraisal of the physical exertion Electrochemical Techniques required to procure a reward. Lynette C. Daws1, Anne M. Andrews2 and Greg A. Gerhardt3 1Department of Physiology and Pharmacology, University of Texas Health Science Center at Egocentric San Antonio, San Antonio, TX, USA 2Semel Institute for Neuroscience and Human Definition Behavior, Hatos Center for Neuropharmacology, California NanoSystems Institute, University of In terms of spatial cognition, an egocentric frame California, Los Angeles, Los Angeles CA, USA of reference is centered on the ego or navigator. 3Department of Anatomy and Neurobiology, Thus, object location can be described in terms of Morris K. Udall Parkinson’s Disease Research angle subtended from the head direction and dis- Center of Excellence, Center for Microelectrode tance from the navigator. Technology, University of Kentucky Medical Center, Lexington, KY, USA

Synonyms Ejecting Current Amperometry; Fast-scan cyclic voltammetry; Definition High-speed chronoamperometry

Term used in neurophysiology to denote a current (either positive or negative) that causes the exit of Definition charged transmitters, drugs, or other compounds of interest from the iontophoretic pipette into the Electrochemical Techniques: A group of analyt- extracellular environment. ical methods based on measuring the current Electrochemical Techniques 587 E produced by oxidation and/or reduction of extracellular milieu. Transporters are also pri- electroactive molecules at an electrode or micro- mary targets for numerous psychotherapeutic electrode surface. Loss or gain of electrons, and addictive drugs. Moreover, neurotransmitter respectively, occurs in response to an applied transporters are implicated in the pathophysiol- potential at the working electrode with respect ogy of psychiatric disease states including to a reference electrode: commonly called depression, anxiety disorders, schizophrenia, voltammetry, amperometry, chronoamperometry, autism, and addiction, as well as Parkinson’s or fast-scan cyclic voltammetry due to the way the and Alzheimer’s diseases. The following sections voltage is applied. The resulting current produced focus on the basic principles of chronoam- by the oxidation/reduction of analytes is propor- perometry and amperometry coupled with micro- E tional to analyte concentrations at the electrode electrodes as they have been applied to advances surface. Historically, electrochemical techniques in the field of psychopharmacology. have been utilized to study chemical reactions, High-Speed Chronoamperometry to Measure but more recently, they have been used to mea- Biogenic Amines Using Carbon Fiber Microelec- sure the concentrations of neurotransmitters and trodes: Chronoamperometry is based on methods other endogenous substances in biological sys- originally described by Cottrell in 1902. Modern tems. Considerable research has been carried electronics and digital data acquisition have led out over the last three decades to develop and to to the ability to measure current at rapid sampling modify electrodes and recording techniques to intervals (1 Hz or faster) permitting high- make these methods selective and sensitive for resolution measurements of neurotransmitter biogenic amine neurotransmitters. Newer ver- transport. To investigate the uptake of biogenic sions of microelectrodes are modified with amines, such as serotonin (5-HT), norepinephrine enzyme layers, such as oxidases that allow for (NE), or dopamine (DA), a carbon fiber micro- the formation of reporter molecules for neuro- electrode (CFE), which is often coated with transmitters and neurochemicals that cannot be Nafion to repel interfering anions, and directly oxidized or reduced at microelectrode a reference electrode are positioned in a suitable surfaces. This has increased the capabilities of buffer solution, cell suspension, synaptosomal electrochemical techniques so that neurotrans- preparation, tissue section, or directly into brain mitters such as glutamate and acetylcholine can (Michael and Borland 2007). The CFE is held at be measured. At this time, measurement of neu- a constant resting potential (typically 0 V) vs. a ropeptides is not within the scope of this Ag/AgCl reference electrode. A 10 Hz square methodology. wave step potential (typically +0.55 V) is applied. This voltage step is selected to encom- pass the range at which most biogenic amines are Principles and Role in oxidized, i.e., lose electrons, histamine being Psychopharmacology a notable exception, as it requires a voltage of +1.0 V for oxidation. The applied voltage is held Introduction: Electrochemical techniques are for 100 ms and this produces a change in oxida- widely used in a variety of research areas, includ- tive current (typically in the range of pA to nA) ing the disciplines of chemistry, physics, and recorded at the CFE. Initially, the current decays biology. Here, we focus on the application of quickly as a function of time, which reflects the electrochemical methods to the field of neuropsy- capacitive or charging current at the surface of chopharmacology and recent advances in this the electrode. The remaining Faradaic current field. In particular, we illustrate some of the produced by each step potential can be integrated breakthroughs made in our understanding of and used to calibrate the CFE against known brain neurotransmitter transporters. These highly concentrations of neurotransmitter prior to use regulated transmembrane proteins are critical for in an experimental setting. The voltage is then clearance of released neurotransmitters from the returned to the resting potential and held for E 588 Electrochemical Techniques

100–900 ms (depending on the neurotransmitter provides a straightforward but powerful means to being measured). This gives rise to a reduction determine the kinetic parameters associated with current. The ratio of the oxidation and reduction transporter function and to tease apart contribu- currents can be used to aid in identification of tions from different transporters, enzymes, and biogenic amines. Currents that result from diffusion to the clearance rates of individual neu- repeated step potentials are measured as rotransmitters. Likewise, factors regulating trans- a function of time to determine the rate of change porter function, such as kinases and growth of neurotransmitter concentrations resulting from factors, can be studied in vivo. The following the action of neurotransmitter transporters. The section provides some examples of how this limit of detection for most biogenic amines by approach has been used to advance chronoamperometry is in the nanomolar range, psychopharmacology. and this technique has found its greatest suc- Transporter Kinetics: High-speed chronoam- cesses in measuring the clearance of exogenously perometry and other electrochemical techniques applied neurotransmitters. A limitation of this have given us the unprecedented ability to inves- approach is that basal levels of neurotransmitter tigate the kinetics of biogenic amine transport are not readily determined because microelec- mechanisms on a second-by-second basis trodes have limited selectivity and other oxidiz- in vitro, ex vivo, and in vivo, the latter in both able species in brain tissue that contribute to the anesthetized and freely moving animals. One of measured current are not easily distinguished the findings that have emerged is that uptake rates from basal neurotransmitter levels from extracel- may be significantly higher and affinities substan- lular fluid. One of the advantages of chronoam- tially lower than previously thought based on perometry is that the high frequency at which radiochemical studies of neurotransmitter trans- recordings are made (1–5 Hz) enhances signal porters (Perez et al. 2006). For example, 5-HT to noise because small changes in current due to uptake rates measured by chronoamperometry in the detection of biogenic amines are not masked synaptosomes (Perez et al. 2006) or in vivo by large and potentially varying background cur- (Daws 2009) are up to 100 times higher than rent (see Michael and Borland 2007). Additional those determined radiochemically. Likewise, the advantages include the spatial (micrometer) res- affinity of the 5-HT transporter (SERT) for 5-HT olution at which recordings are made. There are is 1 mM by chronoamperometry compared to many variations of this approach and these are values in the low nanomolar range determined described in detail in Electrochemical Methods by uptake of [3H]5-HT. The reasons for these for Neuroscience (Michael and Borland 2007). discrepancies are complex; however, some of Applications in Psychopharmacology: the contributing factors have been elucidated Chronoamperometry approaches used by us, and and involve loss of transported neurotransmitter others, stem from the pioneering work of Ralph during the filtration process used for synapto- Adams in the late 1970s and 1980s. In brief, somes, which is necessary for radiometric assay, Nafion-coated CFEs, pre-calibrated to the neuro- but not for direct chronoamperometric measure- transmitter of interest, are exposed to brain tissue ments of uptake ex vivo or in vivo (Perez or implanted stereotaxically into the brains of et al. 2006). Additionally, chronoamperometry anesthetized mice or rats. By coupling CFEs to is typically carried out in synaptosomes or cells glass, multibarrel micropipettes, drugs, or neuro- incubated in oxygenated buffer or in intact respir- transmitters can be exogenously applied directly ing brain tissue. Finally, because changes in neu- to the brain with excellent spatial resolution (e.g., rotransmitter concentration due to transporter the typical active recording areas of CFEs range activity are resolved on a second-by-second from 50 to 300 mm in length and 5–30 mmin timeframe by chronoamperometry, compared to diameter, and micropipettes can be closely posi- a single measurement obtained over minutes by tioned within 300 mm). Bath application or direct radiochemical methods, the entire nonlinear pressure ejection of exogenous neurotransmitter kinetics associated with transport can be resolved Electrochemical Techniques 589 E using chronoamperometry, including initial efficaciously in SERT-deficient mice than in uptake rates. wild-type mice, suggesting the possibility of Biogenic Amine Promiscuity: Studies carried using OCT3 antagonists as novel antidepressants out in the 1960s and 1970s using in vitro uptake or adjuvant therapy (Daws 2009). Subsequent assays of tritiated neurotransmitters gave rise to preclinical studies have shown that the OCT the notion that transporters for the biogenic blocker, decynium-22, enhances the amines, for example, the 5-HT, NE, and DA antidepressant-like activity of SSRIs in wild- transporters (SERT, NET, and DAT, respec- type mice, an effect that was lost in OCT3 knock- tively), take up not only their native neurotrans- out mice (Horton et al. 2013). Decynium-22 also mitter but are capable, albeit with lower affinity, enhanced the effect of an SSRI to inhibit 5-HT E of taking up other neurotransmitters (see Daws clearance. Together, these results suggest that 2009 for review). However, this concept of neu- further investigation of the therapeutic potential rotransmitter transporter promiscuity has only of drugs that target OCT3 is needed. This exam- recently become more widely accepted in our ple of transporter promiscuity is one of the many thinking about central neurotransmission. Studies that have been revealed using voltammetric using chronoamperometry have played approaches (see Daws 2009), and it has wide- a significant part in advancing this idea (see ranging implications for understanding treatment Daws 2009). A recent example comes from stud- responses to numerous psychiatric disorders, as ies in mice lacking one intact copy of the SERT well as sensitivity to abused drugs. gene. These SERT-deficient mice are a useful Regulation of Biogenic Amine Transporters: model for humans carrying variants of the Biogenic amine transporters were once thought to SERT gene that confer constitutively lower be relatively invariant regarding their expression SERT expression and function. Interestingly, and function; however, research over the past humans with lower expressing SERT alleles 20 years has shown that these transporters are show somewhat greater susceptibility to depres- highly regulated at a number of different levels sion and other stress-related disorders on average (Blakely and Edwards 2012). Our understanding and may be less responsive to treatment with of the underlying signaling pathways and 5-HT selective reuptake inhibiting antidepres- neuroadaptive scenarios that regulate trans- sants (SSRIs), such as fluoxetine (Prozac), porters has grown substantially, and much which act to inhibit SERT. One possible expla- research in this area has been carried out using nation for SSRI resistance is upregulation of in vitro systems. Amperometry has been other transporters capable of taking up 5-HT. employed in transfected cell lines to reveal that These transporters thereby buffer the ability of biogenic amine transporters can operate in differ- SSRIs to increase extracellular 5-HT, presumably ent modes, e.g., similar to a gate in an alternating a first step necessary for triggering the cascade of access turnstile, or under other circumstances, events leading to therapeutic benefit. One such like an open channel. Furthermore, studies using promiscuous transporter is the organic cation chronoamperometry have demonstrated that sig- transporter type-3 (OCT3), for which SERT- naling pathways regulating biogenic amine trans- deficient mice have higher expression levels. porters, as identified in vitro, are also at work Like 5-HT, histamine is also a substrate for in vivo. These regulatory pathways include

OCT3; however, it is not a substrate for SERT. those coupled to 5-HT1B autoreceptors, Using high-speed chronoamperometry, hista- alpha2-adrenoceptors, adenosine receptors, dopamine clearance from the extracellular fluid in mine D2 autoreceptors, and interleukin-1 recep- the hippocampus was found to be significantly tors, to name a few (Blakely and Edwards 2012). faster in SERT-deficient mice than in wild-type In the future, in vivo electrochemical techniques mice, a relationship opposite to that for 5-HT can also be used to investigate the therapeutic clearance in these animals. Blockers of OCT3 potential of drugs targeted to sites downstream of were found to inhibit 5-HT clearance more receptors, such as second messengers and kinases. E 590 Electrochemical Techniques

Regulation of transporters by other signaling section focuses on technological advances that molecules, including brain-derived neurotrophic enable the study of fast synaptic neurotransmis- factor (BDNF), neurotrophic growth factor sion, such as glutamatergic signaling, using elec- (NGF), corticosterone, and insulin, has also trochemical techniques. been studied in vivo using amperometric Real-Time (2 Hz) Measurements of Neuro- approaches. Results from these studies are pro- transmission In Vivo Using Enzyme-Based viding vital clues into how stress, nutrition, and Microelectrode Arrays: Numerous advances in aging influence biogenic amine transporter func- electrochemical techniques have now allowed tion, as well as individual variations in responses the measurement of fast excitatory neurotrans- to therapeutics that target these transporters. mission using enzyme-modified microelectrodes Since the same genes code for monoamine trans- (Burmeister et al. 2013 and references within). porters in the central nervous system and the This was not previously possible using standard periphery, assessing transporter function in the electrochemical methods due to the fact that latter by chronoamperometry (and other) tech- some neurotransmitters, such as glutamate, can- niques has been proposed as an accessible bio- not be oxidized or reduced at electrode/micro- marker of brain transporter function (Beikmann electrode surfaces at usable working potentials et al. 2013). For example, differences in SERT (typically <1 V). Microelectrode array (MEA) expression and function in peripheral blood cells technology can now be used for direct in vivo associated with a SERT gene variant of human determination of basal or resting levels of gluta- importance paralleled those previously reported mate and other neurotransmitters, as well as tooccurinthebrain(Singhetal.2012). evoked overflow due to stimulation or behavior- In addition, future studies using in vivo electro- ally induced events (Burmeister et al. 2013). chemical techniques aimed at determining These MEAs are micro-fabricated using photo- how psychotherapeutics exert their effects on lithographic techniques. The design employs brain neurochemistry, why their therapeutic Al2O3 substrates patterned with Pt or Ir electrode actions might be delayed (as is the case with surfaces, which are coated with polyimide layers current antidepressant medications), and what for insulation. The resulting 4–16 recording site compensatory changes might occur in other arrays are modified with enzymes and organic transporter systems have the potential to provide molecules to make them sensitive and selective new information leading to the development of for the reproducible and rapid measurement of novel pharmacologic approaches for the treat- L-glutamate (Glutamate MEAs), which is the ment of psychiatric and neurodegenerative major excitatory neurotransmitter in the CNS. disorders. Recently, MEAs have been manufactured by Summary: This section has focused primarily thousands and routinely exhibit limits of detec- on chronoamperometry to measure biogenic tion for L-glutamate <0.2 mM, with response amine clearance. A brief description of the prin- times of 2 Hz. Early designs employed Nafion ciples underlying this technique and examples of coatings that have now been replaced with meta- its applications to psychopharmacology are phenylenediamine (m-PD) to greatly increase the described. For more comprehensive information selectivity of the measurements, which can detect on fundamental principles and applications, the changes in glutamate from 0.2 to 500 mM with reader is referred to Electrochemical Methods for Pearson’s coefficients >0.99. Despite these Neuroscience (2007) Eds. Michael, A. and advances, weaknesses in MEA designs still Borland, L. Notably, electrochemical techniques, include in vivo lifetimes limited to 30 days, such as chronoamperometry, provide the only enzyme coatings that require two days for curing, means currently available for the study of the response times limited to 2 Hz, and the fact that time-resolved kinetics of neurotransmitter MEAs have higher fabrication costs than CFEs. release and clearance in vivo, in both anesthe- Applications in Psychopharmacology: MEA tized and freely moving animals. The following technology has recently been applied to study Electrochemical Techniques 591 E changes in CNS glutamate release in response to In summary, the electroanalytical techniques L-DOPA-induced dyskinesia (Nevalainen described here can be used to address a large et al. 2013) and in mice that lack the D4 dopamine number of pharmacological questions in anesthe- receptor (Thomas et al. 2008), which is a receptor tized and freely moving experimental animals. implicated in attention deficit hyperactivity dis- In addition, the rapid recording capabilities of order (ADHD). Reliable measures of basal gluta- MEAs allow for the assessment of the kinetics mate have been determined in awake rats, mice, of electroactive and nonelectroactive neurotrans- and monkeys in striatum and prefrontal cortex. mitter release and clearance in vivo, analogous to Using self-referencing recording methods, extra- the aforementioned studies of biogenic amines cellular glutamate can be reliably measured and studied using chronoamperometry in combina- E generally ranges from 5 to 10 mM. In rats, extra- tion with carbon fiber or boron-doped diamond cellular levels of glutamate are diminished by microelectrodes. >50 % with transient application of tetrodotoxin, a sodium channel blocker, and >50 % with local application of a-conotoxin, a calcium channel Cross-References blocker, supporting the idea of neuronal origin of these extracellular glutamate signals. Local ▶ Biogenic Amines application of glutamate transporter inhibitors, ▶ Electrochemical Techniques dl-threo-beta-benzyloxyaspartate (TBOA) or ▶ Glutamate Microelectrode Arrays dl-threo-beta-hydroxyaspartate (THA), increases ▶ Meta-phenylenediamine extracellular glutamate concentrations. Repro- ▶ Microelectrode Arrays ducible potassium-evoked release (1–2 s pressure ▶ Nafion ejection of 50–150 nl of 70 mM KCl) of gluta- ▶ Neurotransmitter Transporters mate ranging typically from 5 to 40 mM has been recorded in regions of the hippocampus, frontal cortex, striatum, and cerebellum of anesthetized References rats, mice, and monkeys. These signals have average rise times of 1–3 s with total time courses Beikmann BS, Tomlinson ID, Rosenthal SJ, Andrews AM of typically 5–12 s. Signals appear to be governed (2013) Serotonin uptake is largely mediated by platelets by Michaelis-Menten-like kinetics, with the rate of versus lymphocytes in peripheral blood cells. ACS Chem Neurosci 4:161–170 decay of the signals increasing as the maximum Blakely RD, Edwards RH (2012) Vesicular and plasma amplitude of the signals increases. Typical rates of membrane transporters for neurotransmitters. Cold clearance of glutamate range from 1 to 10 mM/s Spring Harb Perspect Biol 4:a005595 when measured by MEAs. Potassium-evoked Burmeister JJ, Davis VA, Quintero JE, Pomerleau F, Huettl P, Gerhardt GA (2013) Glutaraldehyde cross- release of glutamate can be repeated at 30 s interlinked glutamate oxidase coated microelectrode vals in most brain areas. In addition, MEAs have arrays: selectivity and resting levels of glutamate in been modified with different enzymes and poly- the CNS. ACS Chem Neurosci 4:721–728 mer coatings to measure other nonelectroactive Daws LC (2009) Unfaithful neurotransmitter transporters: implications for the treatment of psychiatric disorders. neurotransmitters, metabolites, and drugs, includ- Pharmacol Ther 121:89–99 ing but not limited to choline, acetylcholine, glu- Horton RA, Apple DA, Owens WA, Baganz NL, Cano S, cose, aspartate, lactate, peroxide, GABA, Mitchell NC, Vitela M, Gould GG, Koek W, Daws LC dopamine, and ethanol in CNS tissues. Interest- (2013) Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel ingly, MEA technology is the first to enable targets to treat depression. J Neurosci 33:10534–10543 in vivo measures of resting or basal levels of Michael A, Borland L (2007) Electrochemical methods neurotransmitters by virtue of the ability to carry for neuroscience. Taylor & Francis Group, LLC, Boca out self-referencing recordings with this micro- Raton Nevalainen N, Lundblad M, Gerhardt GA, Stromberg I electrode, in addition to stimulus-evoked release (2013) Striatal glutamate release in L-DOPA-induced of neurotransmitters (Burmeister et al. 2013). dyskinetic animals. PLoS One 8:e55706 E 592 Electroconvulsive Therapy

Perez XA, Bianco LE, Andrews AM (2006) Filtration disrupts synaptosomes during radiochemical analysis Electroencephalography of serotonin uptake: comparison with chronoamperometry in SERT knockout mice. J Neurosci Method 154:245–255 Wilhelmus H. I. M. (Pim) Drinkenburg Singh YS, Altieri SC, Gilman TL, Michael HM, Janssen Research & Development, A Division of Tomlinson ID, Rosenthal SJ, Swain GM, Murphey- Janssen Pharmaceutica NV, Beerse, Belgium Corb MA, Ferrell RE, Andrews AM (2012) Differen- tial serotonin transport is linked to the rh5-HTTLPR in peripheral blood cells. Trans Psychiatry 2:e77 Thomas TC, Grandy DK, Gerhardt GA, Glaser PEA Synonyms (2008) Decreased dopamine D4 receptor expression increases extracellular glutamate and alters regulation in mouse striatum. Neuropsychopharmcology 34:436–445 Electroencephalogy; Cortical or brain waves; ECoG; EEG; Neuronal network oscillations; pEEG; qEEG; Surface ﬁeld potentials

Electroconvulsive Therapy Definition Synonyms Electroencephalography refers to a suite of sci- ECT entific methodologies to visualize and analyze the ongoing electrical activity of the brain as fluctuations in voltage, caused by neuronal ionic Definition current flows, which is then reflected in the electroencephalogram or EEG. In contrast to the A procedure in which electrical current is admin- recording of event-related potentials (ERPs), istered via scalp electrodes to induce a brief sei- EEG recording is a passive process during zure. Originally introduced in the 1930s, ECT is which the spontaneous, summed electrical activ- now used primarily to treat severe depression and ity of populations of mainly cortical pyramidal less frequently for mania or catatonia that is neurons is measured, also capturing subcortical refractory to medication. Treatments are given and glial cell contributions. The EEG is charac- under light anesthesia, with a usual course of terized by an unparalleled high temporal resolu- 6–12 treatments given two or three times tion, but has a low spatial resolution and, as such, a week. In addition to the risks of anesthesia, complements other brain imaging techniques like the major adverse effect is memory loss, which PET, SPECT, CT, MRS, or fMRI, some of which can be mitigated by electrode placement. may be recorded in parallel with EEG. While electrical brain signals were first recognized by Richard Caton in 1875 in animals (Feeble currents of varying direction pass Electroencephalogram through the multiplier when the electrodes are placed on two points of the external surface of the Definition skull: Caton 1875), recording of EEG is now routinely done in humans and animals alike, Recording of the brain’s global electrical activity, with most applications using noninvasive elec- obtained using electroencephalography. trodes (on the surface of the scalp and epidural, respectively) via widely available, inexpensive digital recording and storage equipment. Since Cross-References the pioneering days of Caton, the field has been under development with increasing ▶ Event-Related Potential levels of understanding of the meaning of Electroencephalography 593 E brain oscillations. Over the past decades, EEG via depth electrode recording (Buzsáki 2006). research was boosted mainly by technological When targeting local field potentials of subcor- progress such as the availability of more powerful tical nature, such signals can be recorded when computers or the extension of the technology of electrodes are positioned through the skull, recording electric currents to recording the aimed at recording the oscillatory electrical cur- dynamics of magnetic fields in magnetoencepha- rents generated by specific deep brain (sub) lography (MEG). Lastly, the development of structures or layers thereof. Several different more advanced analysis algorithms has contrib- frequency ranges can be distinguished, and uted to the value of EEG both as a clinical and their functional interpretation is strongly linked a research tool (e.g., concordance, cross- to the function of the neuronal substrate and E frequency coupling, exact low-resolution electro- related neurochemistry. Whereas cortical sig- magnetic tomography (eLORETA)), although nals are not coming from the deeper axon action clinical sleep EEG is sometimes still annotated potentials per se, they are nonetheless under, for by hand. example, thalamic control, receiving inputs from the reticular activating system. Hence, the EEG is indirectly also controlled by brainstem Neuronal Origin of the Cortical EEG structures governing vigilance (Niedermeyer Signals and Lopes da Silva 2005)andcanbe a remarkable translational biomarker as illus- EEG neuroimaging is based on the estimation of trated in EEG applied to sleep-wake studies. the cortical current density from scalp recordings of multiple surface electrodes and one reference electrode (i.e., on isoelectric part of the Pharmaco-EEG (pEEG) body such as mastoid bone or earlobes). Electric potentials when recorded from the scalp or epi- Notwithstanding the high heritability of EEG dural are contingent to the current density that is parameters, the EEG must be considered as generated in the cortex by pyramidal neurons a nonspecific indicator of cerebral function, with and their postsynaptic processes: action poten- a high sensitivity to changes in both environmen- tials result in changes in electromagnetic gradi- tal and internal states. Consequently, effects of ents over the cortical layers. The structural psychoactive pharmacological agents will have organization of the cerebral cortex consists of to be interpreted with care: the field of pharmaco- vertical columns with apical dendrites, which electroencephalography (pEEG) therefore con- are oriented towards the skull with axons cerns the precise description and the quantitative projecting to deeper brain structures. As analysis of the effects of substances on the central a consequence, the EEG as detected by scalp nervous system (CNS) by means of neurophysi- electrodes is mainly formed by the excitatory ological and electrophysiological methods used and inhibitory postsynaptic potentials on den- within the framework of clinical and experimen- drites and cell bodies (Niedermeyer and Lopes tal pharmacology, neurotoxicology, therapeutic da Silva 2005). The EEG can be recorded as research, and associated disciplines. Pharmaco- microvolt signals, when there are sufficient and EEG studies aim to precisely predict response sufficiently synchronized potentials that reach after administration of a psychoactive drug, mak- the surface as a volumic summation. The mac- ing implicit use of qEEG methodology. The con- roscopic EEG signal is characterized by bipolar sistency (i.e., high within-subject test-retest cyclic changes in potential with oscillations reliability) and the nature of the empirical obser- from 20 to over 1,000 ms. The appearance and vations captured by the pEEG method have entrainment of different rhythms in the EEG established pEEG as a suitable psychopharmaco- is caused by the characteristics of the synchro- logical instrument. As intersubject variability nized local network firing, as can be shown may be negatively influenced by the subject’s E 594 Electroencephalography characteristics (e.g., age and gender) and lifestyle representing a particular granularity of the EEG (e.g., caffeine, alcohol, and nicotine are thought signal. As a “mathematical microscope,” it pro- to lastingly perturb the EEG), a crossover design vides information on frequency in relation to time is indicated for pEEG studies to control for intervals. confounds. Different frequency bands can be distinguished in an electroencephalographic spectro- gram, each of which may reflect a certain Principles functional brain activity (e.g., theta rhythms recorded during a subject’s active exploration) EEG Acquisition or involvement of a certain neuronal substrate Standardization of EEG acquisition methodology (e.g., hippocampus and theta rhythm). and harmonization of EEG analysis are crucial Bandings may be influenced by pharmacolog- when comparing outcomes of EEG studies in ical agents individually or in conjunction with a meaningful way. To this end, the International other bandings. Harmonized frequency ranges Pharmaco-EEG Society (IPEG) has published for spectral analysis in pEEG research (spectral guidelines for the recording and evaluation of power in mV/Hz) include delta (d) 1.5 to <6.0 Hz; pEEG data in man (Jobert et al. 2012), which theta (y) 6.0 to <8.5 Hz; alpha-1 (a1) 8.5 to provide an elaborate description and explanation <10.5 Hz; alpha-2 (a2) 10.5 to <12.5 Hz; of the presently preferred pEEG methodology: beta-1 (b1) 12.5 to <18.5 Hz; beta-2 (b2) 18.5 digital recording settings, amplification and fil- to <21.0 Hz; beta-3 (b3) 21.0 to <30.0 Hz; tering, calibration, electrode positions, and envi- gamma (g) 30.0 to <40.0 Hz; and total power ronmental and recording conditions are specified. 1.5 to <30.0 Hz. In addition, the label sigma Table 1 provides an overview of minimum (s) describes waves between 12.50 and requirements for studies in humans (IPEG guide- <15.00 Hz, while epsilon (e) has been used for lines for animal pEEG studies are under waves of <0.5 Hz. With ultra-low and ultrahigh construction). oscillations being largely uncovered, through Figure 1 shows the putative neurophysiologi- promising EEG research areas (Buzsáki 2006), cal mechanisms in rats and humans for the gen- a further expansion and subdivision of the gamma eration of ongoing electroencephalographic band to include higher frequencies has not yet rhythms in RSc and RSo recording conditions been harmonized: “low” gamma may cover (resting state eyes closed and eyes opened, 30–45 Hz with “high” gamma covering respectively). 60–90 Hz. A further subdivision could be into gamma-1 (g1), gamma-2 (g2), and gamma-3 EEG Analysis (g3) for frequencies up to 200 Hz, while frequen- The transformation of an EEG signal from the cies at 200 Hz and above have been labeled time domain into the frequency domain is one of lambda (l). The functional importance of the most used analyses: in applying fast Fourier gamma waves is increasingly recognized, espe- transformation (FFT), it is implicitly assumed cially for cognitive processes; however, reliable that a (stationary) signal can be split up as measurement of (high) gamma from scalp elec- a finite sum of weighted pure frequency compo- trodes in humans is not straightforward and nents. The resulting graphical representation dis- requires careful consideration (Jobert et al. 2012). plays the spectral characteristics or so-called Artifact elimination is mandatory for correct power spectrum of the EEG signal. The wavelet quantitative analysis of the pEEG. Optimal transform is a kind of improved FFT, except that recording conditions can ensure that artifacts are it operates on a multi-scale rather than on a single infrequent and occur only accidentally. Artifacts scale basis (i.e., only time or frequency). This can be of physiological origin and must be iden- multi-scale feature enables decomposition of tified and/or eliminated either online during the a signal into a number of scales, each scale recording or off-line, preferably aided by Electroencephalography 595 E

Electroencephalography, Table 1 Minimum requirements for the recording of pEEG studies in humans (Adapted from Jobert M, Wilson FJ, Ruigt GSF, Brunovsky M, Prichep LS, Drinkenburg WHIM (2012). Guidelines for the recording and evaluation of Pharmaco-EEG data in man – International Pharmaco-EEG Society (IPEG). Neuropsy- chobiology 66(4):201–220. Copyright by S. Karger AG, Basel) EEG recording Sampling rate 500 Hz equipment A/D conversion 16 bits High-pass 0.5 Hz (0.01 Hz recommended) filtering Low-pass 70 Hz (roll-off of at least 12 dB/octave) filtering Notch filter Usage avoided; otherwise 50 or 60 Hz (dependent on the power supply frequency) E Pre-amplifier 100 MΩ at 50 Hz impedance Common mode 90 dB rejection Electrodes Electrode Balanced impedance across all electrode sites impedance Number and At least 21 electrodes placed according to the 10–20 system or the extended 10–20 placement system (10 % system) in case >21 electrode are used Type Ag/AgCl or equivalent in terms of electrode drift and DC resistance Montage Monopolar against a common reference

Reference Should be modiﬁable post hoc, (Cz,A1,A2, average mastoids)

Ground AFz EOG Vertical and horizontal for artifact identiﬁcation ECG Recommended EMG Recommended Experimental Adaptation It is recommended to make the subject familiar with the recording conditions and design and procedures during a separate recording session conditions Recording Sound-attenuated room environment Constant dimmed light (approximately 40 lx) or light level deﬁned by the computer monitor used for task presentation Constant room temperature: 20–23 C (68–73 F) Any major disturbances should be logged subject in a (semi-) reclined comfortable position or in an upright position facing a computer monitor (for studies that also include a task) Design Double-blind placebo-controlled crossover design is recommended for acute studies in healthy subjects For multiple dose and patients studies, the design should be adapted to the objectives Recording time Baseline and a number of post-drug recording time points to be driven by drug PK; at

points least one time point around Tmax plus at least 3 time points covering the decline in the PK cure (usually multiples – e.g., 1, 2, 4, and 8 h)

If Thalf 12h, then a 24-hour overnight time point should be considered Time of day Preferably in the morning Crossover repeat tests be done at the same clock time and under the same conditions Recording RT (5-min vigilance controlled, eyes closed)

conditions RSc (5- to 15-min resting condition, eyes closed)

RSco (10-min resting with alternate eyes open and eyes closed) Storage Local storage The proprietary format of each EEG recording equipment conditions Export/import European data format “plus” format Signals Raw data without transformation Automatic artifact rejection is optional E 596 Electroencephalography

Electroencephalography, Fig. 1 Putative neurophysi- eyes closed) and RSo (resting state with eyes closed) ological mechanisms for the generation of ongoing elec- condition. The text in the ﬁgure suggests that acetylcho- troencephalographic rhythms in the rat (top drawings) and line promotes the desynchronization of spontaneous ongo- in the human (bottom drawings) brain. A sketch of the ing EEG rhythms by a direct, local effect on cortical EEG rhythms is reported for the RSc (resting state with neurons (Adapted from Babiloni et al. 2013) polygraphic recordings of concurrent ocular (the percentage of power contained in (EOG), cardiac (ECG), muscular (EMG), behav- a frequency band relative to the total spectrum) ioral, breathing, swallowing, and sweating activ- relationships or cross-frequency coupling, which ity. Special care should be taken in those studies captures how oscillations in various frequency where higher-frequency bandings (i.e., beta and bands interact. Furthermore, the EEG has been gamma) are of interest, since the EEG signals of instrumental for neurophysiological characteri- skull recordings may be contaminated by muscle zation of complex neuronal network and brain activity and sampling rates of 2 kHz or higher circuit’s dynamic and functional connectivity may be required for adequate artifact modeling (Stam and van Straaten 2012). Finally, identiﬁcation. three-dimensional functional imaging of brain Advanced analyses using qEEG include, for electrical activity is possible using LORETA example, concordance analysis, which is used to (low-resolution electromagnetic tomography), determine regional brain activity based on abso- which is based on multichannel scalp EEG record- lute (the amount of power in a frequency band at ing without a priori knowledge about the putative a given electrode) and relative power number of discernible source regions. LORETA is Electroencephalography 597 E

Electroencephalography, Fig. 2 Examples of state eyes closed) condition, (b) a striking slow-wave non-pathological spontaneous and drug-induced state activity, abolishing frontal alpha waves after administra- changes in EEG. Epochs of scalp EEG as simultaneously tion of 1 mg iv clonazepam (a benzodiazepine used as recorded from four midline surface electrodes according anti-epileptic), (c) drug-induced (fast) beta oscillations. to the international 10–20 system for electrode montage Major grid indicates 1 s, minor ticks 200 ms; calibration showing (a) a gradient of occipital alpha rhythm (spindle bar indicates 100 mV; * indicates R-R interval ECG activity at Oz and Pz approximately at 10 Hz) fading out in (Adapted from Boeijinga 2010) the more anterior cortical domains under a RSc (resting capable of locating the most probable cortical and with psychotropic drugs (Boutros et al. 2008; subcortical sources for frequency bands. LORETA John and Prichep 2006; Saletu et al. 2006). images can also be computed relative to normative Next, hypotheses on underlying mechanism voxel values, so sources can be quantified as drug- were put forward, such as Saletu’s keylock prin- induced deviations from age-expected norms ciple, i.e., an optimal psychotropic induces pEEG (Pascual-Marqui et al. 2011). changes that are opposite to the differences between patients and controls as induced by the drug, thus normalizing the EEG (Saletu Role in Psychopharmacology et al. 2006). Over the past decade, the field of qEEG-based Historically, the EEG has been instrumental in personalized medicine has provided new insights neurological applications, most specifically in the in subtyping of psychiatric populations and in diagnosis and characterization of phenomena predicting pharmacological treatment response, related to epilepsy and sleep. Clinical use of recovery, and outcome. A growing body of evi- EEG thus focused on disorders that at some dence suggests that treatment selection, outcome, stage may be accompanied by paroxysmal and prediction of evolution of disorders can be discharges or epileptiform EEG activity, such assisted by translational qEEG tools. as panic, dementia and delirium, aggression, The use of EEG and more specifically pEEG and ADHD (Boutros et al. 2008) and in defining and studying sleep-wake processes, polysomnographic diagnosis of sleep disorders ranging from activated states, through passive (Jobert et al. 2013). Its application in psychiatry wakefulness, sleep, anesthesia, and even has been promising but controversial and limited. coma, including all possible related pathologies, By using qEEG, a more refined analysis became constitutes a separate important application with available to further characterize aberrant brain specific requirements for recording, analysis, and activity in schizophrenia, anxiety, and mood dis- scoring of sleep stages (e.g., polysomnography, orders and, moreover, to determine interactions see Jobert et al. 2013). Non-REM sleep E 598 Electroencephalography

Electroencephalography, Fig. 3 Examples of drug- demonstrates that alpha frequency band increases in induced pEEG mapping. Panel (a): Left column, descrip- healthy volunteers (Adapted from Boeijinga et al. 2002). tive qEEG topography for the alpha frequency band for Panel (b): Pharmaco-EEG profile of scopolamine inferen- a single subject without drug (bottom image with his tial nonparametric testing (n = 12) of differences has contours every 25 mV) and on clonazepam (top row, left been carried out on an electrode-by-electrode basis with panel). The crossover design allows subtraction (bottom, decreases in several bands at frequencies above eight middle image) of EEG variables; finally inferential non- Hertz and increases in delta, compared to placebo. Note parametric testing of differences (mapping for groups) that overall, a slowing in EEG can be deduced: the bio- confirms drug-induced significant decreases. Topograph- marker can be used to test reversal by (new) cognition- ical maps are constructed by interpolation for the values enhancing drugs, and hence a single phase I trial in a on 19 standard electrode positions + Oz and eight inter- co-administration design, known as scopolamine model, mediate leads for active treatment. Example at the right predicts efficacy at an early stage (Adapted from mapping for a member of the class of acetylcholine ester- Boeijinga 2010) ase inhibitors, donepezil; a similar statistical procedure

(stages I to IV), REM sleep, and wakefulness are Human pEEG each characterized by distinct EEG oscillations (e.g., slow-wave sleep for non-REM stages III Pharmaco-EEG studies are applicable when and IV) and can be pharmacologically a substance is indicated to have CNS effects at inﬂuenced. As sleep stages are partly scored therapeutic or pharmacologically relevant dose based on EEG characteristics, one has to be cau- levels in all phases of preclinical and clinical tious for pharmacological dissociations, such as research and may answer questions in clinical after administration of hypnotic doses of benzo- pharmacology as well as in therapeutic research diazepines, when the pEEG is dominated by beta or drug discovery and development. Figure 2 frequencies that normally are a hallmark of wak- exempliﬁes pEEG changes as can be found ing vigilance levels rather than sleep. under non-pathological conditions. lcrecpaorpy599 Electroencephalography a Vehicle Vehicle Donepezil Donepezil + + + + Vehicle Scopolamine Vehicle Scopolamine Scopolamine (0.64mg/kg) 100 Donepezil (3mg/kg) 100 100 100 −350 % 90 90 90 90 80 80 80 80 100 70 70 70 70 −144.3% 75 60 60 60 60 −50% 50 50 50 50 50 25 40 40 40 40 0 30 30 30 30 −25 20 20 20 20 −50 10 10 10 10 −75 1 1 1 1 −100 15 3045 6075 90105 120135 15 3045 6075 90 105 120 135 15 3045 6075 90105 120 135 15 3045 6075 90 105120 135 01530609010512045 75

100 100 100 100 100 90 90 90 90 75 80 80 80 80 50 70 70 70 70 25 60 60 60 60 0 50 50 50 50 FL FR −25 40 40 40 40 −50 PR 30 30 30 30 PL −75 20 20 20 20 −100 OL OR 10 10 10 10 01530609010512045 75 1 1 1 1 15 3045 6075 90105 120 135 15 3045 6075 90 105120 135 15 3045 6075 90105 120 135 15 3045 6075 90105 120 135

EEG Frequency Oscillations (Hz) 100 100 100 100 100 90 90 90 90 75 % Changes in EEG & Frequency power 80 80 80 80 50 70 70 70 70 25 60 60 60 60 0 50 50 50 50 −25 40 40 40 40 −50 30 30 30 30 −75 20 20 20 20 −100 10 10 10 10 01530609010512045 75 1 1 1 1 Time (15 min epochs) 15 3045 6075 90 105 120 135 15 3045 6075 90 105 120135 15 3045 6075 90105 120135 15 3045 6075 90105 120 135 Time post-administration (15 min epochs)

Electroencephalography, Fig. 4 (continued) E E E 0 Electroencephalography 600

Electroencephalography, Fig. 4 Examples of drug-induced pEEG spectral and challenge effects on the spectral content by donepezil. Panel (b) shows the change in connectivity mapping in reversal studies in the rat. Panel (a) shows for each of three functional connectivity (amplitude coherence) between six electrode positions for the recording positions (frontal right, parietal right, occipital right) the changes in spectral delta frequency band for the four drug conditions (from top to bottom) on the eight content (y-axis from 0 to 100 Hz) of the rat EEG after administration (x-axis 15 min 15-min epochs after administration (from left to right). The widths of the edges epochs) of either vehicle, scopolamine, donepezil, or both donepezil and scopolamine indicate the proportion of changes from baseline (0–50 %, 50–100 %, and as compared to baseline (scopolamine at 0.64 mg/kg s.c., donepezil at 3 mg/kg s.c., 100–150 %), where red color represents increases and blue color indicates decreases n = 8 each condition). Right line graphs show changes in spectral bands for delta for in connectivity. Note the “reversal” of the scopolamine-induced disruptions in con- each drug condition and brain region. Note the “normalization” of the scopolamine nectivity by donepezil (Adapted from Ahnaou et al. 2013) Electroencephalography 601 E

Pharmaco-EEG brain mapping is suited to psychoactive reference and test compounds. assess topographical changes induced by A multitude of functional EEG measures has CNS-active compounds. Usually, the topograph- been investigated mostly in rats and mice, ical distribution of spectral parameters and error ranging from simple spectral power to probabilities (probability mapping) are advanced connectivity parameters with high- displayed. Figure 3a shows how a neuropharma- density EEG. Reversal studies can also be reli- cological comparison between placebo and drug- ably carried out in animals, comparable to induced EEG effects on the alpha-1 and alpha-2 phase I clinical studies (Fig. 4): disruption of bands can be mapped for two drugs from different brain function and concomitant EEG changes drug classes when using a crossover study design: can consistently be achieved through pharma- E clonazepam (a benzodiazepine used as anti- cological or behavioral challenges as well as by epileptic) was shown to reduce values over transgenic manipulation. Such modeled ani- almost the whole scalp, whereas donepezil mals are then available for reversal testing (AchE inhibitor) induced increases mainly on with novel test compounds targeting specific the posterior scalp. Extending pEEG mapping to brain neurochemistry systems. other frequency bands obviously provides com- The translational validity of animal pEEG in plementary information, which yields a more drug discovery and development research seems comprehensive picture of the action of a drug on dependent on the psychoactivity and/or neuronal brain neurophysiology (e.g., slowing of EEG; see substrates under investigation: for studying Fig. 3b). Pharmaco-EEG mapping further allows effects of drugs on sleep-wake processes, rodent for the use of challenge agents, the EEG effects pEEG has shown high predictive and transla- whereof can then potentially be reversed by test tional validity, while reversal of several specific compounds (Fig. 3b). neurotransmitter manipulations has been successfully validated as well (e.g., Fig. 4). The pEEG is thought to have significant poten- Animal pEEG tial as a translatable intermediate biomarker of central pharmacodynamic activity; however, Animal EEG research has made valuable contri- its potential could not yet be realized due to lack butions to neurophysiological science: as animal of standardization of methodology between aca- neurophysiological studies are open to invasive, demia and industry, rendering data pooling and deep brain recording and stimulation paradigms meta-analyses flawed and assessment of trans- as well as other in vivo electrophysiological latability problematic (Wilson et al. 2014). techniques (e.g., multi- or single unit recordings), the neuronal circuits and oscillations generating systems underlying the pEEG can Summary be studied in detail. Furthermore, the use of animal pEEG has been instrumental in drug The EEG and pEEG thus offer in both preclinical discovery and development: next to characteriz- and clinical settings a low-cost, noninvasive, ing the functional effect or potential efficacy of and widely available translational assessment test compounds, it is also used to assess pharma- of neurophysiological processes with a very codynamic (PD) characteristics – along with high time resolution and with the possibility of separate pharmacokinetic (PK) data- or drug- combined use with diverse structural/functional drug interactions – and to monitor side effects neuroimaging techniques as well as with neuro- (e.g., sedation) and toxicity (e.g., epileptic psychological/behavioral assessments. Lastly, seizures). in line with our increasing understanding of the Databases of pEEG and polysomnography complexity of neuronal circuits and oscillations studies in rodents hold EEG signatures (“fin- in relation with their closely interlinked neuro- gerprints”) of a broad collection of chemistry (John and Prichep 2006), the EEG E 602 Electrospray Ionization remains one of the key technologies for psycho- Ffytche DH, Freeman J, van Gerven JMA, Hirata K, pharmacological research in both humans and Hegerl U, Kinoshita T, Knott VJ, Lopes Da Silva FH, Matousek M, Mucci A, Nottage JF, Olbrich S, animals. Saletu B, Stancak A, Strik WK, Wise RG (2012) Guidelines for the recording and evaluation of pharmaco-EEG data in man – International Pharmaco- Cross-References EEG Society (IPEG). Neuropsychobiology 66:201–220 Jobert M, Wilson FJ, Roth T, Ruigt GS, Anderer P, ▶ Classification of Psychoactive Drugs Drinkenburg WHIM, Bes FW, Brunovsky M, ▶ Event-Related Potential Danker-Hopfe H, Freeman J, van Gerven JM, ▶ Electroencephalography Gruber G, Kemp B, Klo¨sch G, Ma J, Penzel T, Peter- ▶ son BT, Schulz H, Staner L, Saletu B, Svetnik Function of Delta Waves V (2013) Guidelines for the recording and evaluation ▶ Function of Slow and Fast Alpha Waves of pharmaco-sleep studies in man – International ▶ Polysomnography Pharmaco-EEG Society (IPEG). Neuropsychobiology ▶ Sleep 67:127–167 ▶ John ER, Prichep LS (2006) The relevance of QEEG to the Translational Neuroimaging evaluation of behavioral disorders and pharmacologi- ▶ Translational Research in Drug Discovery cal interventions. Clin EEG Neurosci 37:135–143 Niedermeyer E, Lopes da Silva FD (2005) Electroenceph- alography, basic principles, clinical applications, and related fields, 5th edn. Lippincott Williams & Wilkins, References Philidelphia Pascual-Marqui RD, Lehmann D, Koukkou M, Kochi K, Ahnaou A, Huysmans H, Drinkenburg WHIM (2013) Anderer P, Saletu B, Tanaka H, Hirata K, John ER, EEG-network oscillations: a target for screening Prichep L, Biscay-Lirio R, Kinoshita T (2011) drugs with cognition-enhancing and antipsychotic Assessing interactions in the brain with exact potential. Poster presented at Society for Neuroscience low-resolution electromagnetic tomography. Philos meeting, San Diego Trans A Math Phys Eng Sci 369:3768–3784 Babiloni C, Infarinato F, Aujard F, Bastlund JF, Saletu B, Anderer P, Saletu-Zyhlarz GM (2006) EEG Bentivoglio M, Bertini G, Del Percio C, Fabene P, topography and tomography (LORETA) in the classi- Forloni G, Herrero Ezquerro MT, Noe` FM, Pifferi F, fication and evaluation of the pharmacodynamics of Ros-Bernal F, Zerlang Christensen D, Dix S, psychotropic drugs. Clin EEG Neurosci 37(2):66–80 Richardson J, Lamberty Y, Drinkenburg W, Rossini Stam CJ, van Straaten EC (2012) The organization of PM (2013) Effects of pharmacological agents and physiological brain networks. Clin Neurophysiol other challenges on electroencephalographic rhythms 123:1067–1087 in preclinical studies: towards translational models for Wilson FJ, Leiser SC, Ivarsson M, Christensen SR, drug discovery in Alzheimer’s Disease. Clin Bastlund JF (2014) Can pharmaco- Neurophys 124(3):437–451 electroencephalography help improve survival of Boeijinga PH (2010) Electroencephalography. In: central nervous system drugs in early clinical develop- Stolerman IP (ed) Encyclopedia of psychopharmacol- ment? Drug Discov Today 19(3):282–288 ogy. Springer, Berlin Boeijinga PH, Calvi-Gries F, Dermazieres A, Luthringer R (2002) Planning of pharmacodynamics trials: spec- ificities and possible solutions and interpretation of Electrospray Ionization drug effects on EEG. Methods Find Exp Clin Pharmacol 24(suppl C):17–26 Boutros NN, Thatcher RW, Galderisi S (2008) Synonyms Electrodiagnostic techniques in neuropsychiatry. In: Yudofsky SC, Hales RE (eds) The American psychi- ES; ESI; Nanospray atric publishing textbook of neuropsychiatry and behavioral neurosciences, 5th edn. American Psychi- atric Publishing, Arlington Buzsáki G (2006) Rhythms of the brain. Oxford Univer- Definition sity Press, New York Caton R (1875) The electrical currents of the brain. Br A process in which ionized species in the gas Med J 2:278 Jobert M, Wilson FJ, Ruigt GSF, Brunovsky M, Prichep phase are produced from a solution via highly LS, Drinkenburg WHIM, Babiloni C, Boeijinga PH, charged fine droplets, by means of spraying the Elevated Plus Maze 603 E solution from a narrow-bore needle tip at atmo- spheric pressure in the presence of a high electric field (1,000–10,000 V potential).

Cross-References

▶ Mass Spectrometry ▶ Metabolomics ▶ Neuropeptidomics E ▶ Posttranslational Modiﬁcation ▶ Proteomics Elevated Plus Maze, Fig. 1 Published studies using the ▶ Two-Dimensional Gel Electrophoresis elevated plus maze test per year, according to the search performed (July 2013) on the PubMed site http://www. ncbi.nlm.nih.gov/pubmed/)

Elevated Plus Maze papers so far (Fig. 1), is likely owing to its numerous advantages, namely, economy, rapidity, sim- Antonio Pádua Carobrez, Grasielle Clotildes plicity of design, and bidirectional drug Kincheski and Leandro Jose´ Bertoglio sensitivity, coupled with the fact that it does not Departamento de Farmacologia, CCB, require lengthy training procedures or the use of Universidade Federal de Santa Catarina, food/water deprivation or electric shock (Pellow Floriano´polis, SC, Brazil et al. 1985; Lister 1990; Rodgers et al. 1997).

Synonyms Principles and Role in Psychopharmacology Elevated x-maze; Plus-maze test; EPM The EPM stands as one of the most popular in vivo animal tests currently in use not only for Definition drug discovery/development but also for investigating basic neurobiological mechanisms under- The elevated plus maze (EPM) is a reliable mea- lying fear and anxiety. As shown in Fig. 2, the surement tool to investigate anxiety-related EPM is also useful as a post hoc test to investigate defensive behaviors in rodents, particularly rats the emotionality of rodents subjected to genetic, and mice. Derived from the study of Montgomery biochemical, and behavioral interventions. Other (1955) concerning exploratory patterns, the EPM interesting applications of the EPM include the creates an approach-avoidance conﬂict in which preclinical investigation of anxiety-related the environmental novelty is capable of simulta- behaviors during drug withdrawal states and the neously evoking curiosity and fear (Handley and study of learning and memory processes concur- Mithani 1984). An extensive pharmacological, rent with fear and anxiety in rodents exposed to physiological, and behavioral validation of the the EPM (Carobrez and Bertoglio 2005). EPM as an animal test of anxiety in rats was The behavioral measures routinely scored performed by Pellow and colleagues (1985) and during the 5-min EPM session are the frequency further extended to mice by Lister (1990). of open- and enclosed-arm entries and the The EPM is an example of a task based on the amount of time spent on the open and enclosed observation of rodents’ spontaneous behavior. Its arms. These data are used to calculate the popularity, with almost 5,000 indexed published percentage of open-arm entries {%OAE; E 604 Elevated Plus Maze

Elevated Plus Maze, Fig. 2 Main focus of studies published using the elevated plus maze test in 2012 according to search performed on PubMed site (http://www.ncbi.nlm.nih. gov/pubmed/)

[open entries/(open + enclosed entries)] Â 100} can be an important source of variation among and the percentage of time spent in open arms {% dominant and subordinate males and females. OAT; [open time/(open + enclosed time)] Â 100}. As a consequence, either false-negative or false- As illustrated in Fig. 3, there is a clear positive results can occur if these important enclosed-arm preference. Under the influence of caveats are not taken into account. For instance, an anxiogenic-like drug, a further reduction in the in spite of having similar defensive responses, open-arm exploration is observed. When anxio- mice and rats show a different level of general lytics are administered, treated animals display exploratory activity in the EPM test (mice have significantly more open-arm exploration than been more active than rats). Anxiety scores also controls. In this context, it is worth mentioning tend to change with age, apparently reflecting that the efficacy of the EPM test in discriminating distinct brain development and/or the behavioral anxioselective compounds has been increased repertoire of the species. with the adoption of more ethologically based Some procedural variables have also been analysis, i.e., the measurement of some acts and shown to impact on the EPM baseline level. postures such as stretched attend, head dipping, They include housing conditions, circadian and grooming (Cruz et al. 1994). For instance, the rhythm, illumination level, duration of testing, frequency of stretched-attend postures toward the apparatus construction, definition of behavioral open arms (Fig. 3c, g) can be used as an index of measures, prior handling/stress, and prior test risk assessment, a close behavioral dimension experience. Together with organismic variables, related to anxiety (Rodgers et al. 1997; Carobrez these are the main sources of interlaboratory var- and Bertoglio 2005). The anxioselective discrim- iability in the use of the EPM (Bertoglio and inative property confers to the EPM test the pre- Carobrez 2005). Based on the fact that behavioral dictive validity required to screen putative responses and pharmacological effects observed compounds and to identify alternative pharmaco- in the EPM are under the influence of these vari- logical interventions in anxiety field. ables (Hogg 1996), it is imperative that laboratories using or planning to use this test dedicate Methodological Variables time and effort in order to define the optimal The main organismic variables of interest in the experimental conditions before starting their EPM test are species, strain, age, gender, and respective studies (Rodgers and Cole 1994). estrus cycle including lactation, all of which have been proven to interfere with its behavioral Potential Limitation of the EPM Task baseline level (Rodgers and Cole 1994). Further- It has been pointed out that within the rodent more, different social roles in the rodent group repertoire of defensive behaviors, the EPM is Elevated Plus Maze 605 E

Elevated Plus Maze, Fig. 3 (a) The rat elevated plus (e.g., the benzodiazepine midazolam, MDZ) increase maze consisted of two opposite open arms (surrounded by open-arm exploration (e and f) and reduced stretched- a small ledge) and two enclosed arms, about 50 cm above attend postures (g), those with anxiogenic properties the ground. Its use to assess anxiety is relatively simple: (e.g., pentylenetetrazole) elicit the opposite outcome. one may score the number of entries and the time spent on One possible complication that an animal might not the open arms (b). Besides these spatiotemporal measures, come out because it is inherently inactive (and not anx- there are more subtle postures related to anxiety that are ious) can be dealt with by scoring the number of enclosed- collectively known as risk assessment behaviors, such as arm entries, an index of general exploratory activity in this the stretched attend (c). An “anxious”- type animal is one test (d and h). Values are expressed as mean Æ S.E.M. that displays risk assessment behavior very often and Asterisks indicate a statistically significant difference rarely ventures out on the open arms. In general, as (P < 0.05) from controls shown on the right panels, whereas anxiolytic drugs E 606 Elimination Half-Life able to detect inhibitory avoidance and risk Cruz AP, Frei F, Graeff FG (1994) Ethopharmacological assessment. The expression of overt defensive analysis of rat behavior on the elevated plus-maze. Pharmacol Biochem Behav 49:171–176 behaviors, such as freezing or flight, however, is Handley SL, Mithani S (1984) Effects of alpha- not necessarily detectable. Although both adrenoceptor agonists and antagonists in a maze- responses could be elicited by anxiogenic-like exploration model of “fear”-motivated behaviour. drugs, freezing might also be confounded with Naunyn-Schmiedeberg’s Arch Pharmacol 327:1–5 Hogg S (1996) A review of the validity and variability of the enclosed-arm reduced activity found in sub- the elevated plus maze as an animal model of anxiety. jects treated with anxiolytics at sedative-like Pharmacol Biochem Behav 54:21–30 doses. Likewise, flight behavior induced by Lister R (1990) Ethologically-based animal models of anxiogenics could also be confounded with the anxiety disorders. Pharmacol Ther 46:321–340 Montgomery KC (1955) The relation between fear higher open-arm activity normally seen in ani- induced by novel stimulation and exploratory behav- mals treated with anxiolytic-like drugs. Overall, ior. J Comp Physiol Psychology 48:254–260 this limitation can also be applied as a note of Pellow S, Chopin P, File SE, Briley M (1985) Validation caution when testing genetically modified organ- of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth isms in the EPM. In fact, it might be extended to 14:149–167 all organismic and procedural variables listed Rodgers RJ, Cole JC (1994) The elevated plus-maze: above. pharmacology, methodology and ethology. In: Cooper Automatic scoring of behavioral measures has SJ, Hendrie CA (eds) Ethology and psychopharmacology. Wiley, Chichester, pp 9–44 been proposed to avoid subjective bias. Although Rodgers RJ, Cao BJ, Dalvi A, Holmes A (1997) Animal these computer programs permit the analysis of models of anxiety: an ethological perspective. Braz spatiotemporal patterns of exploration in the EPM, J Med Biol Res 30:289–304 some behavioral measures relevant to risk assessment cannot be automatically quantified (Carobrez and Bertoglio 2005). Moreover, incon- sistent results obtained in this test may indicate that the associated emotional state and reaction is Elimination Half-Life critically dependent on stimulus parameters (Hogg 1996; Rodgers et al. 1997). Clearly, the behavioral Synonyms expressions displayed in the EPM test represent a combination of exploratory and avoidance Biological half-life; Terminal half-life behaviors, as well as general activity, all of which are influenced by both genetic and environmental factors (Bertoglio and Carobrez 2005). Definition

Theplasmahalf-lifeofadrug(t½) is the time Cross-References necessary to reduce the plasma concentration by half, for example, to decrease from ▶ Anxiety 100 to 50 mg/L. The knowledge of the half-life ▶ Defensive Behaviors is useful for the determination of the frequency ▶ Psychopharmacology of administration of a drug (the number of ▶ Risk Assessment intakes per day) for obtaining the desired plasma concentration. Generally, the half-life of a particular drug is independent of the dose References administered. In certain exceptional cases, it varies with the dose: it can increase or decrease Carobrez AP, Bertoglio LJ (2005) Ethological and temporal analyses of anxiety-like behavior: the elevated according to, for example, the saturation of plus-maze model 20 years on. Neurosci Biobehav a mechanism (elimination, binding to plasma Rev 29:1193–1205 proteins, etc.). Emotion and Mood 607 E

Cross-References Principles and Role in Psychopharmacology ▶ Area Under the Curve ▶ Bioavailability The modulation of mood and discrete emotional ▶ First-Order Elimination Kinetics states are common targets of psychopharmacol- ▶ Pharmacokinetics ogy. Additionally, agents designed to address neuropathological processes or improve cognitive functioning often have effects on mood, sometimes to enough of an extent as to inﬂuence Emetine patients’ willingness to take the agent. Thus, E accurate measurement of mood and emotion is Definition critical to psychopharmacological research. Unfortunately, there is no accepted “gold stan- An alkaloid that inhibits protein synthesis by dard” for assessing mood and emotion. However, interfering with mRNA-ribosome interaction. the science of measuring mood and emotion has grown in sophistication in recent years, and attention to the details of assessment can substantially increase one’s ability to detect pharmacological Emotion and Mood inﬂuences on emotional processing.

David H. Zald Assessing Basic Emotions Department of Psychology and Psychiatry, Basic emotion assessments are appropriate in Vanderbilt University, Nashville, TN, USA situations where a pharmacological agent is intended to directly regulate or reduce the occurrence of a basic emotion such as fear or anger, as Synonyms might occur during treatment of a phobia or bor- derline personality disorder. Basic emotions may Affect; Feeling also warrant assessment when administering pharmacological agents with extremely fast pharmacokinetics, since such agents may directly Definition induce a discrete emotion, such as fear or euphoria. At the broadest level, an emotion is a highly Because basic emotions are most frequently valenced experiential state. More precisely, emo- seen in response to characteristic situations or tions comprise coordinated neural, neuromuscu- stimuli, it is essential to assess these emotions in lar/expressive, and experiential responses to relation to the occurrence of such triggering meaningful stimuli or events. In the affective events. This can be accomplished either through sciences, the term emotion (or basic or discrete retrospective self-report ratings or through emotion) is used to specifically refer to strong laboratory-based exposure paradigms in which transient states, such as anger, disgust, fear, sad- the individual is exposed to triggering stimuli or ness, surprise, and joy, which have a quick onset, situations. Retrospective ratings have the advan- a brief duration, clear behavioral tendencies, tage of potential aggregation over multiple time definable expressive and autonomic characteris- periods and triggering events in the person’s tics, and occur in response to species typical everyday life, but provide limited, if any, ability antecedents. These discrete emotions are distin- to standardize the frequency, qualitative nature, guished from moods, which are valenced experi- or intensity of triggering events across conditions ential states that occur over longer temporal or individuals. Furthermore, the verification and spans, often lasting minutes or hours. coding of such events can be highly subjective E 608 Emotion and Mood and difficult to reliably code. Additionally, unless of dimensional models of valence (or approach- the person is fitted with an ambulatory psycho- avoidance) and arousal (Levenson 1988). physiological and video recording system, it is Although laboratory exposure techniques not possible to collect any additional objective have a number of strengths for the assessment measures of the emotion. of basic emotions, they suffer from two In contrast, laboratory exposure techniques major shortcomings. First, the laboratory events can be highly standardized and allow the collec- may be weak and somewhat unnatural approxi- tion of data time-locked to the triggering event. mations of real-life triggering events. Second, it By time-locking self-report ratings, an individual is often difficult to aggregate over multiple expo- does not have to evaluate already long-past expe- sures in the laboratory setting due to habituation. riences to determine ratings. More importantly, In such cases, the reliability of the assessment is time-locking allows the use of objective mea- often compromised. sures, which can complement or in some cases replace self-report ratings. These objective mea- Assessing Mood sures consist of coding or direct measurement of In most psychopharmacological contexts, the facial muscle activity and psychophysiological assessment of more enduring mood states is measurements of correlates of sympathetic and more relevant than assessing basic emotions. parasympathetic autonomic activity. Because For instance, the depressive disorders are diag- basic emotions are accompanied by specific pat- nosed based on sustained enduring mood states, terns of facial muscle movement (indeed, this is rather than individual discrete periods of emo- a common criterion for a basic emotion), codings tion. Similarly, the goal of treatment for depres- of facial expression are frequently used as sion is to alter these enduring mood states, as markers of emotion. Detailed coding systems of opposed to targeting discrete emotions. Such facial expressions are well validated and can be mood states may be less intense than the basic applied to video recordings of participants emotions, but they do not require assessments (Ekman et al. 2002). An alternative approach is that are time-locked to triggering events. to measure facial muscle activity with electromy- Self-report remains the only viable option in ography (EMG). EMG can detect weak activity most studies of mood, because there are few objec- of muscles even in cases in which a full expres- tive measures of mood. A first question arises sion is not completed. However, it is important in regarding which mood terms a subject should using this technique to record from a number of rate. Factor analytic studies indicate that mood muscle groups simultaneously, as single muscle data are marked by two higher-order factors groups are often multidetermined. For instance, (Watson and Tellegen 1985), which are, respec- the corrugator supercilii muscles above the orbits tively, labeled positive affect (PA) and negative are sensitive to anger, but also show increased affect (NA). (Note: The use of the term “affect” activity during exposure to ambiguous or difficult here refers to the subjective mood factor, rather stimuli (Pope and Smith 1994). Psychophysio- than to an individual’s observable expressed emo- logical measures, such as electrodermal tion, which is how the term “affect” is frequently response, blood pressure, blood volume, heart used in psychiatric settings.) PA reflects a person’s rate, detailed analysis of electrocardiograms, level of pleasurable engagement with the environ- respiration, and skin temperature, are all useful ment. High states of PA are characterized by terms as objective measures of the presence of an emo- such as interested, excited, and determined, which tional experience. By combining psychophysio- denote positive behavioral engagement. NA com- logical measurements, it is possible to observe prises a general factor of subjective distress, with some degree of autonomic patterning specific to high states of NA marked by descriptors such as basic emotions. However, true discriminant distressed, nervous, and hostile. Taken together, validity is difficult to achieve with these mea- PA and NA account for 50–75 % of the common sures, which often show properties characteristic variance of mood. Emotion and Mood 609 E

An alternative dimensional schema for under- provides a widely used measure of mood standing mood states has been proposed by Russell that taps the relatively pure factor structure of (1980), who identifies a bipolar valence dimension PA and NA. The scale includes 20 mood labels (unpleasant-pleasant) and a second dimension of marking high (activated) PA and NA states and arousal. This schema has some advantages, partic- has been repeatedly found to be sensitive to indi- ularly when examining immediate responses to vidual differences in both current and long-term stimuli, where one often sees a clear inverse rela- mood. There are, however, a few important lim- tionship between positive and negative experi- itations of this type of scale. First, as originally ences. However, when aggregating over multiple designed, the PANAS does not measure time points, or measuring longer retrospective mood states associated with reduced PA E periods, the inverse relationship between positive or NA. Specifically, terms such as fatigue and negative experience weakens. This indepen- (which appears to reflect an absence of PA) or dence allows for the study of separable influences calm (which appears to reflect an absence of NA) on PA and NA (which is not feasible with a single are not assessed. Subsequent measures, such as bipolar valence dimension in which pleasant and the expanded version of the PANAS (the negative states are measured in opposition to each PANAS-X), have attempted to capture these other). An important distinction can also be made “low activation” markers. Yet, low activation between the Russell model and the PA/NA model markers do not possess as pure a factor structure of Watson and Tellegen, in that the experience of as high activation markers of PA and NA. This pleasantness or unpleasantness may be seen as occurs because terms such as boredom or tired a consummatory response to stimuli or events. In not only reflect an absence of PA but are also contrast, PA and NA are more motivational in experienced as unpleasant, while states such as nature, with clear links to approach and avoidance. serenity or calm not only reflect an absence of NA This consummatory vs. motivational separation but are also experienced as pleasant. Because of parallels Berridge’s (1996) distinction between this, low activation states require direct assess- wanting and liking as applied to mesolimbic ment and should not be inferred by simply reverse dopamine and opioid functions. This distinction scoring high NA or high PA terms. This issue between wanting and liking also appears useful takes on importance when we consider that in monitoring drug-induced mood changes. many medications and street drugs are taken to For instance, the Drug Effects Questionnaire alleviate feelings such as fatigue or to induce (Fischman and Foltin 1991)askssubjectsto calm. Treatment studies provide further evidence separately rate drug wanting and drug liking, and of the need to directly assess low activation these two ratings often show distinct patterns of states, as antidepressants can produce differential correlations and differential time courses follow- effects on low activation vs. high activation PA ing drug exposure. states (Tomarken et al. 2004). Interestingly, alter- PA and NA show different temporal patterns. ations in low activation states figure prominently Individuals typically show at least a moderate level in the subjective effects of certain drugs. For of PA, with variability occurring around their own instance, alcohol researchers frequently utilize traitwise mean level. In contrast, NA is typically the Biphasic Alcohol Effects Scales (Martin very low, with spikes occurring in response to et al. 1993), which is a 14-item scale containing specific negative or potentially negative events. two factors: (1) a stimulant factor that corre- This has implications for experimental designs, sponds to high PA, which increases during the because the ability to observe a pharmacological rising limb of blood alcohol levels and (2) a sed- agent’s impact on NA may be limited in the labo- ative factor that corresponds to an absence of PA ratory environment if the person is not exposed to (i.e., low activation), which increases during the potentially unpleasant experiences. descending limb of blood alcohol levels. The positive and negative affect schedule A second issue with the pure factor approach (PANAS), developed by Watson et al. (1988), implemented by the PANAS arises because some E 610 Emotion and Mood important mood states reflect combinations of the subjective effects of specific drugs is the different levels of PA and NA. For instance, sad- Addiction Research Center Inventory (ARCI) ness can be viewed as a combination of reduced developed by Haertzen et al. (1963), which mea- PA and heightened NA. Given the importance of sures subjective responses to a number of specific sadness to the affective disorders, it is often classes of drugs, including morphine, LSD, and essential to capture subjective states such as sad- amphetamine, and among other symptoms tries ness, and the continued use of measures, such as to capture a euphoric-dysphoric continuum. With the Profile of Mood States (McNair et al. 1981), 550 true-false items, the inventory is problemat- which includes a Depression-Dejection scale, ically long for use as a real-time measure, so attests to this. In the NA domain, there is also many investigators will restrict the questions to sometimes utility in examining lower-order fac- just those related to the specific drug of interest. tors, such as anxiety or hostility. In doing so, it is important to determine to what extent observed Types of Rating Scales associations are specific to the lower-order factor An important, and often overlooked, issue in vs. reflecting the higher-order factor of NA more studies of emotion and mood involves how to generally. For instance, even a scale such as the have participants rate their moods. Most studies State-Trait Anxiety Inventory (Spielberger have utilized either visual analog scales (VAS) or et al. 1983), which is often treated as a specific Likert scales (LS). VAS consist of two verbal measure of anxiety, captures elements of general anchor descriptors that are placed on either end distress and thus cannot be used to draw conclu- of a continuous line. Respondents provide ratings sion about a specific subfactor of NA. on VAS by indicating the point on the line that best represents the intensity of their current psy- Drug-Specific Assessments chological experience. VAS may be considered Studies examining the psychological effects of to provide interval-like data, in that they provide drugs of abuse require attention to the specific rank-order information about rating values and subjective effects of the agent. In particular, equal spacing exists between neighboring values because of the intensity of basic emotion or along the entire scale continuum. Unfortunately, mood states induced by drugs of abuse, typical because the continuum lacks verbal descriptors, it mood scales may fail to appropriately capture is impossible to ascertain the qualitative intensity such experiences or may demonstrate ceiling that corresponds to an intermediary rating. This effects (in which too many subjects give maximal means that intermediary ratings made by differ- ratings). For instance, ratings of joy may fail to ent individuals are not readily comparable. In capture the intensity of euphoric states. Several contrast, to the VAS, LS consist of numeric scales are in circulation that attempt to rectify this points arranged along a discrete continuum, problem by asking at least one question related to with intensity descriptor labels placed at both euphoria or related experiences. For instance, anchor points and at the intermediary numeric Van Kammen and Murphy (1975) developed the points. These labels have the advantage of lead- Amphetamine Interview Schedule to capture sub- ing individuals to use the intermediate ratings in jective responses to amphetamine and include an a more qualitatively similar way. However, such item for euphoria, as well as related experiences scales are problematic, in that unless the intensity of closeness to others, confidence, and overall descriptors are truly equidistant, the applied feeling good. The Drug Effects Scale (Fischman numeric values do not represent the true quanti- and Foltin 1991) includes a rating of “feeling tative (interval-like or ratio-like) differences in high” that may tap euphoric effects. However, ratings. This is particularly problematic for bipo- the term “feeling high” is ambiguous, as it can lar scales (for instance, those running from also refer to a broad range of other subjective unpleasant to pleasant), in that studies examining experiences, including perception of altered real- ratings of verbal descriptors have revealed that ity. The most comprehensive scale for capturing the magnitude differences of terms typically used Emotion and Mood 611 E

Emotion and Mood, Fig. 1 Example of bipolar scales of pleasantness in a visual analog, Likert, and labeled magnitude format

to mark the low to moderate intensities cover all may contribute to error in the measurement of a smaller distance than terms used to mark the mood. However, such response artifacts do not moderate to the most intense anchors. This means invalidate mood ratings; they merely make it less a change in ratings between two descriptors in the accurate. Moreover, in some cases, it is possible to lower intensity part of the scale cannot be con- correct response artifacts or identify individuals sidered equivalent to a change in two descriptors with invalid data by speciﬁcally assessing for at the higher part of the scale (Fig. 1). response biases. In summary, there continue to be Recent research has led to the development of challenges inherent to measures of emotion and labeled magnitude scales (LMS), which attempt mood, but through careful research design these to address the weaknesses of the VAS and LS measures can substantially contribute to psycho- (Lishner et al. 2008). LMS utilize a visual analog pharmacological research. scale framework, but include descriptors that are placed along the scale at empirically determined Cross-References intervals derived from rating studies of the intensity descriptors. Such scales also often use “most ▶ Addiction Research Center Inventory imaginable” instead of “extremely” as the highest ▶ Affective State intensity anchor in order to limit ceiling effects. ▶ Amphetamine To date, the LMS approach has not been widely ▶ Appetitive Responses used in psychopharmacological research, but this ▶ Aversive Stimuli type of approach can be easily integrated into ▶ Fear existing scales. However, it may be necessary to ▶ Liking and Wanting verify that the factor structure of the existing ▶ Mesolimbic System measures is consistent when moving from an LS ▶ Opioid or VAS format to an LMS format. ▶ Reward Intensity Response Biases A ﬁnal consideration in self-report data relates to References potential response artifacts that lead an individual to respond in a manner that is not representative of Berridge KC (1996) Food reward: brain substrates of their true level of current mood. Response biases, wanting and liking. Neurosci Biobehav Rev 20:1–25 Ekman P, Friesen WV, Hager JC (2002) Facial action including acquiescence biases, nay-saying biases, coding system (FACS), a human face. Research carelessness, and socially desirable response sets, Nexus eBook, Salt Lake City E 612 Emotional Learning

Fischman MW, Foltin RW (1991) Utility of subjective- effects measurements in assessing abuse liability of Emotional Numbing drugs in humans. Br J Addict 86:1563–1570 Haertzen CA, Harris HE, Belleville RE (1963) Develop- ment of the Addiction Research Center Inventory Definition (ARCI): selection of items that are sensitive to the effects of various drugs. Psychopharmacologia Difficulties experiencing emotions, resulting in 4:155–166 Levenson RW (1988) Emotion and the autonomic nervous social distance, lack of interest in activities. system: a prospectus for research on autonomic specificity. In: Wagner HL (ed) Social psychophysiology and emotion: theory and clinical applications. Wiley, New York, pp 17–42 Lishner D, Cooter AB, Zald DH (2008) Addressing measurement limitations in affective rating scales: devel- Empirically Based Treatments opment of an empirical valence scale. Cogn Emot 22:180–192 Definition Martin CS, Earleywine M, Musty RE, Perrine MW, Swift RM (1993) Development and validation of the biphasic alcohol effects scale. Alcohol Clin Exp Res Specific treatment interventions that have dem- 17:140–146 onstrated effectiveness in clinical trials or inter- McNair DM, Lorr M, Droppleman LF (1981) Manual ventions that are based on scientifically proven profile of mood states. Educational and Industrial Test- ing Service, San Diego methods of change. Pope LK, Smith CA (1994) On the distinct meanings of smiles and frowns. Cogn Emot 8:65–72 Russell JA (1980) A circumplex model of affect. J Pers Cross-References Soc Psychol 39:1161–1178 Spielberger CD, Gorusch RC, Lushene RE (1983) Manual for the state-trait anxiety inventory. Consulting Psy- ▶ Double-Blinded Study chologists Press, Palo Alto ▶ Randomized Controlled Trials Tomarken AJ, Dichter GS, Freid C, Addington S, Shelton RC (2004) Assessing the effects of bupropion SR on mood dimensions of depression. J Affect Disord 78:235–241 van Kammen DP, Murphy DL (1975) Attenuation of the euphoriant and activating effects of d- and Encoding l-amphetamine by lithium carbonate treatment. Psychopharmacologia 44:215–224 Watson D, Tellegen A (1985) Toward a consensual struc- Definition ture of mood. Psychol Bull 92:426–457 Watson D, Clark L, Tellegen A (1988) Development and The acquisition of new information that leads to validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol the establishment of at least a short-term 54:1063–1070 memory.

Emotional Learning Endocannabinoid Signaling

Definition Definition

A type of learning that shares one important char- Alterations in synaptic plasticity that are pro- acteristic, namely, that the learning involves duced by changes in endocannabinoid activation acquisition of an emotional mental state. of CB1 cannabinoid receptors. Endorphin 613 E

receptors. Three genes encoding a range of Endocannabinoids endogenous opioid peptides have been identiﬁed: pro-opiomelanocortin, preproenkephalin, and Definition prodynorphin.

Natural ligands for cannabinoid receptors, the receptors that mediate the pharmacological Cross-References effects of the active compounds in the cannabis plant (marihuana). Among them is anandamide. ▶ Dynorphins ▶ Endorphin E ▶ Enkephalins Cross-References

▶ Cannabinoids and Endocannabinoids Endophenotype

Definition Endocytosis An aspect of a phenotype that can in principle Definition be related to underlying a genetic predisposition to a disorder and which provides a partial model A process by which a substance gains entry into or biomarker for a recognized human disease the cell without passing through the plasma mem- state and related aspects of temperament. It is brane; it involves invagination (the formation of a marker for a heritable pathological condition a furrow) of the plasma membrane followed by and may also be present in non-affected relatives membrane fusion by which an intracellular vesi- at a higher rate than in the general population. cle is formed. In this way, proteins that are incorporated in the plasma membrane can end up in the membrane of an intracellular vesicle. Cross-References

▶ Animal Models for Psychiatric States ▶ Genetically Modiﬁed Animals Endogenous Factors

Definition Endorphin Internally generated inﬂuences on behavior. Definition

This term (derived from endo-morphine) is in pop- Endogenous Opioid ular use to refer to any endogenously produced and released opioid substance. It was originally deﬁned Definition for scientiﬁc use where it refers to only the small group of endogenous opioid peptides derived by The term “endogenous opioid” represents any peptidases from the proopiomelanocortin gene, substance produced by the body (to date these which contains a single copy of the 31 amino are all peptides) that interacts with opioid acid peptide, b-endorphin, along with several E 614 Enemas other biologically active peptides. Other endor- phins are shorter fragments of b-endorphin. Engram

Definition Cross-References The material substrate or record of a particular ▶ Opioids item of memory. Also referred to as memory trace.

Enemas Enkephalinase

Definition Definition

Enema is the procedure of introducing liquids into Enkephalinase is a neutral aminopeptidase enzyme the rectum and colon via the anus. Enemas are (EC 3.4.24.11), initially thought to be responsible usually carried out as a treatment for constipation. only for degradation of released enkephalins. It does, however, metabolize other peptides, and enkephalins are also subject to degradation by other peptidases. Nonetheless, direct application Energy Balance of enkephalinase inhibitors has been shown to produce opioid-like actions, probably due to enhance- Definition ment of ▶ endogenous opioid signaling.

The body maintains energy balance (EB) if energy intake (calories ingested and absorbed) matches energy expenditure (calories utilized by Enkephalins the body through basal metabolism, thermogenesis, and activity). If energy intake exceeds energy Definition expenditure, a positive energy balance is achieved and excess calories are stored. Con- Two enkephalin (“in the head”) pentapeptides versely, if energy expenditure exceeds energy were the first endogenous opioids discovered in intake, a negative energy balance is achieved 1975. They both contain the same amino acids in and energy stores (in adipose tissue) are utilized. the first four amino terminal positions followed Sustained energy imbalance produces changes in by either leucine (“leu-enkephalin”) or methio- body weight and composition. nine (“met-enkephalin”) at the carboxy-terminal. Multiple copies of both peptides are contained in the large peptide precursor, preproenkephalin. Somewhat longer oligopeptide enkephalins have Energy Metabolism been purified from various tissues, representing incomplete peptidase processing of the large pre- Definition cursor leu-enkephalin which is also contained in the N-terminal sequence of ▶ dynorphins. Chemical energy has to be provided for brain function in the form of glucose and oxygen; gly- colysis and mitochondrial respiratory chain activ- Cross-References ity are necessary to synthesize adenosine triphosphate (ATP). ▶ Opioids Environmental Enrichment and Drug Action 615 E

Cross-References Entacapone ▶ Methylenedioxymethamphetamine (MDMA) Synonyms

E-a-cyano-N,N-dietyl-3,4-dihydroxy-5- Enterohepatic Cycling nitrocinnamamide Definition

Definition Numerous drugs undergo elimination via the bile E in the unchanged or conjugated form. Drugs Entacapone (E-a-cyano-N,N-dietyl-3,4-dihydroxy- eliminated in the bile are available for absorption 5-nitrocinnamamide) is a catechol-O- in the gastrointestinal tract. This reentry into the methyltransferase (COMT) inhibitor, used for the body after “elimination” via the bile results in the treatment of Parkinson’s disease in conjunction “recycling” of drug and prolongs the time with L-DOPA. Entacapone prevents COMT from required for the drug to be irreversibly eliminated metabolizing L-DOPA, the dopamine precursor, in from the body. the periphery. Entacapone is always used in combination with ▶ L-DOPA for the treatment of Parkinson’s disease, especially in those patients Cross-References showing end-of-dose “wearing-off” signs. Entacapone is also available in a triple combination ▶ Area Under the Curve with L-DOPA and ▶ carbidopa, the DDC inhibitor, ▶ Bioavailability to further increase the half-life of L-DOPA. ▶ Elimination Half-Life ▶ First-Order Elimination Kinetics ▶ Pharmacokinetics Cross-References

▶ Environmental Enrichment and Drug Anti-Parkinson Drugs Action

Mary E. Cain1 and Michael T. Bardo2 1Department of Psychology, Kansas State Entactogen University, Manhattan, KS, USA 2Center for Drug Abuse Research Translation Synonyms (CDART), College of Arts & Sciences, University of Kentucky, Lexington, KY, USA Empathogen

Synonyms Definition Stimulus enrichment and drug effects Entactogens are drugs, including MDMA (Ecstasy) and other MDxx structure compounds, that cause distinctive prosocial, emotional, and Definition sensory effects in users. Most of them are substituted amphetamine compounds of the Environmental enrichment is a manipulation in phenethylamine class. which subjects are exposed to different E 616 Environmental Enrichment and Drug Action environments that vary in the amount of stimulus most critical for producing the neurobiological novelty. In the typical preclinical procedure, effects related to learning and memory. Social rodents are housed in either an enriched condition stimulation alone is not sufﬁcient to produce neu- (EC) with novel objects and social cohorts or an robiological changes similar to those observed isolated condition (IC) without objects or with enrichment. Overall, this research suggests cohorts. In order to determine the relative contri- that cohorts, novel objects, and handling are all bution of novel objects and social cohorts, essential for robust enrichment. While neurobio- a separate group can also be housed in a social logical effects of enrichment are evident after just condition (SC) with social cohorts, but without 4 days of enrichment, the effects are more con- novel objects. While enrichment is applied typi- sistent and reliable when rats are assigned to their cally during the periadolescent period of devel- respective environments after weaning and opment, it produces effects across the life span housed for 30 or more days. and it is reversible. Effects on Drug Action In addition to enrichment altering performance Current Concepts and State of on a variety of measures of learning and memory, Knowledge enrichment also alters the effects of a variety of drugs of abuse (Bardo and Dwoskin 2004). Sev- Effects on Learning and Memory eral studies have examined the effects of enrich- The amount of stimulation received during child- ment on amphetamine-induced hyperactivity. EC hood and adolescence has profound effects on rats display greater amphetamine-induced hyper- behavioral and neurobiological development activity than IC rats following an acute injection (Renner and Rosenzweig 1987). In rats, enriched of amphetamine. However, with repeated injec- environments produce numerous neuroanatomi- tions of amphetamine, IC rats display greater cal changes, including increases in cortical locomotor sensitization than EC rats. Similar weight, cortical thickness, size of neuronal cell results have been observed with cocaine and bodies and nuclei, number of glial cells, number nicotine. of dendritic spines, and number of synapses per Interestingly, enrichment also appears to neuron. Most likely as a result of these neurobi- enhance conditioning to an amphetamine-paired ological changes, enrichment also improves per- context. Using the conditioned place preference formance on several measures of learning and (CPP) procedure, which is a measure of drug memory. Differences are evident in some of the reward, EC rats display greater amphetamine most basic behaviors, including activity in an CPP than IC rats. Similarly, using a low dose of inescapable novel environment and startle reac- amphetamine (0.3 mg/kg), context-dependent tivity. In general, as task complexity increases, conditioned hyperactivityisobtainedinEC the difference in performance increases between rats, but not in IC rats. Moreover, when the rate EC and IC rats (Renner and Rosenzweig 1987). of extinction of conditioned hyperactivity is For example, while EC and IC rats do not differ in measured, EC rats extinguish at a faster rate the acquisition of operant lever press behavior, than IC rats across a range of amphetamine EC rats perform better than IC rats in tests of doses. These results suggest that, in general, spatial memory. EC rats process contextual con- EC rats display a greater ability than IC rats to ditioning cues more rapidly and display better acquire and extinguish contextual conditioning discrimination between conditioned stimuli of drug effects. when compared to SC rats (Barbelivien Numerous studies have examined the effects et al. 2006). of enrichment on self-administration of stimu- Early research on environmental enrichment lants, opiates, and sedatives. When drugs are examined a variety of control conditions to deter- available via the oral route, male EC rats mine if any one component of enrichment was the increase their barbiturate consumption, but not Environmental Enrichment and Drug Action 617 E

amphetamine (0.03 mg/kg/infusion) on a continuous reinforcement schedule, EC rats self- administered less amphetamine than IC rats; there were no differences between EC and IC rats at higher unit doses. A separate group of rats was trained to lever press for amphetamine on a progressive ratio schedule in which the number of lever presses required to earn a drug infusion increased until the rats stopped responding (i.e., breakpoint). As shown in Fig. 2, the E breakpoint was significantly lower for EC than Environmental Enrichment and Drug Action, IC rats at the low unit dose, but not at the higher Fig. 1 Mean number of active lever responses for oral 10 % ethanol across five consecutive 30-min sessions in unit dose. These results suggest that enrichment EC, SC, and IC rats using a two-lever operant conditioning decreases the reinforcing effect of amphetamine, procedure. There was a main effect of group, with EC rats but only at low unit doses. self-administering significantly less ethanol than IC rats; It is possible that the difference between EC SC rats did not differ significantly from the two other groups. There was no difference between EC and IC rats and IC rats in amphetamine self-administration in the number of responses on the inactive lever (which using low unit doses may reflect a difference in had no programmed consequence), although the number the rate of extinction or a difference in the rein- of inactive responses was negligible (~2 responses per statement threshold. The rationale behind this session; results not shown) (From Deehan et al. 2007) possibility is that, at the beginning of each drug self-administration session, rats begin responding their amphetamine consumption, when com- in a drug-free state. If a unit dose is too low, the pared to male IC rats. Interestingly, female responding may simply extinguish similar to EC rats decrease their barbiturate consumption what occurs when saline is substituted for drug. when compared to female IC rats, suggesting However, if several low dose infusions are earned that sex can moderate the effects of enrichment. in rapid succession, total drug intake may accu- EC males also consume orally more cocaine and mulate beyond some minimum threshold, thus ethanol than male IC rats. The amount of oral engendering reliable responding within the ses- ethanol consumption in male EC, SC, and IC rats sion. Based on this notion, the decrease in also has been examined using a two-lever oper- amphetamine self-administration at a low unit ant procedure in which one lever delivered 10 % dose in EC rats could represent either an acceler- ethanol and the other lever had no programmed ated rate of extinction within the session or an consequence. EC rats responded less than IC increase in the reinstatement threshold. A recent rats for oral 10 % ethanol; SC rats were interme- study using the reinstatement procedure found diate between EC and IC rats (Deehan et al. that EC rats extinguished responding faster than 2007,seeFig.1), thus suggesting that enrich- IC rats when amphetamine was replaced with ment may alter the reinforcing effects of oral saline (Stairs et al. 2006). When responding was ethanol itself. reinstated following a noncontingent amphet- Intravenous drug self-administration offers an amine priming injection, IC rats reinstated drug- advantage over the oral route because it elimi- seeking responses following a low dose prime, nates the possibility that differences in taste reac- whereas EC rats only reinstated drug-seeking tivity may complicate interpretation of the results responses following a high dose prime. The obtained. Several studies indicate that environ- higher reinstatement threshold in EC rats, taken mental enrichment decreases the self- together with a more rapid rate of extinction, may administration of low unit doses of amphetamine result in a loss of responding within the session, and cocaine. In one initial study in which rats thus explaining the enrichment-induced reduc- were trained to lever press for a low unit dose of tion in drug intake. E 618 Environmental Enrichment and Drug Action

Environmental Enrichment and Drug Action, or 0.1 mg/kg/infusion (right panel). Asterisk (*) represents Fig. 2 Mean number of amphetamine infusions earned a signiﬁcant difference from IC rats tested at the same unit by EC, SC, and IC rats on a PR schedule of reinforcement dose, p < 0.05 (From Bardo and Dwoskin 2004) using a unit dose of either 0.03 mg/kg/infusion (left panel)

Effects on Neurobiology Involved in Drug as indexed by the velocity of uptake of [3H] Action dopamine uptake into mPFC tissue slices. Numerous studies have explored the neurobio- Measurements of DAT protein expression logical mechanisms that contribute to the ability revealed that EC rats have less DAT than IC rats of enrichment to decrease the reinforcing effect at the cell surface. Additionally, a recent study has of drugs of abuse. Environmental enrichment shown that EC rats display a reduction in postsyn- increases thickness of the cortex, primarily by aptic dopamine D1 receptors in mPFC (Del Arco enlarging the size of neuronal cell bodies, et al. 2007). The enrichment-induced reduction in increasing the density of dendritic spines and pre- and postsynaptic dopaminergic cellular pro- increasing the number of glial astrocytes. Meta- cesses in mPFC may reflect a compensatory bolic activity is also enhanced, as revealed by an decrease due to repeated stimulation of this corti- increase in the number of mitochondria and oxy- cal system by enriching stimulation. genated capillary blood volume (Renner and Studies have shown that environmental Rosenzweig 1987). While these cellular changes enrichment also alters the neurochemical effects also occur in subcortical regions such as the stri- of various drugs of abuse. For example, when atum, hippocampus, and nucleus accumbens, the challenged with acute amphetamine, EC rats prefrontal cortex appears to be especially sensi- show a greater release of dopamine in the nucleus tive to enrichment. accumbens measured by in vivo microdialysis The medial prefrontal cortex (mPFC) has been compared to IC rats. This enrichment-induced implicated in the reinforcing effect of abused change is not specific to amphetamine, but drugs, likely due to its interconnections with lim- appears to occur across various drugs of abuse. bic structures such as the anterior cingulate cortex Alterations in reward-relevant brain regions and nucleus accumbens. Recent work has demon- likely play a role in the differential sensitivity of strated that dopamine activity in mPFC is altered EC and IC rats to self-administer drugs of abuse. in EC rats compared to IC rats (Zhu et al. 2005). In addition to dopamine, enrichment alters These investigators examined functional activity drug-induced glutamate release as measured by of the dopamine transporter (DAT). Compared to microdialysis (Rahman and Bardo 2008). Gluta- IC rats, EC rats have decreased DAT function mate is an excitatory amino acid that has been Environmental Enrichment and Drug Action 619 E implicated in drug reward. When challenged with A more direct assessment of the effects of amphetamine, EC rats show greater extracellular enrichment on human development and health- levels of glutamate in the nucleus accumbens related risk was conducted by Raine et al. (2003). compared to IC rats. Within the mPFC, EC rats Children aged 3–5 years received enrichment or also have increased glutamatergic tone compared control treatment and were assessed subsequently to IC rats. This latter finding may be important in their young adulthood for personality disor- from a drug abuse perspective because ders. Enrichment consisted of training in physical glutamatergic activity is not only important in health, exercise, and multimodal enrichment prodrug reward, but it may also be involved with vided by toys, art, handicrafts, drama, and music behavioral inhibitory processes that become dys- to improve verbal skills, visuospatial coordina- E functional during the addiction cycle. While the tion, and memory. As young adults, enriched effects of enrichment on the dopaminergic and subjects had lower scores for schizotypal person- glutamatergic systems contribute to the ality, antisocial behavior, and criminal behavior reinforcing effect of drugs of abuse, additional (including drug-related charges) compared to research is necessary to determine the interaction control subjects. These results suggest that envi- between these systems and the mechanism for the ronmental enrichment during development pro- ability of environmental enrichment to decrease tects against the emergence of drug abuse and sensitivity to drugs of abuse. associated personality disorders later in life. Fur- ther research is needed to determine what neuro- Application to Humans biological alterations are associated with these Teachers and educators are generally aware of long-term behavioral effects of enrichment. the important role of enriching environments for promoting learning in children, adolescents, and young adults. In addition, there is considerable Cross-References evidence that enriching stimulation, as provided by exercise and learning, protects against many ▶ Conditioned Drug Effects neurodegenerative diseases that can occur later in ▶ Conditioned Place Preference and Aversion life. While preclinical research indicates that ▶ Operant Behavior in Animals enrichment also protects against drug abuse vul- ▶ Psychostimulant Dependence and Its nerability, there is a paucity of information that Treatment addresses this issue specifically in humans. None- ▶ Psychostimulants theless, genetic studies using twin concordance ▶ Reinstatement of Drug Self-Administration or familial assessment strategies indicate that the ▶ Self-Administration of Drugs heritability of drug abuse is only around ▶ Sensitization to Drugs 40–60 %, thus implicating a substantial role for ▶ Sex Differences in Drug Effects environmental factors. A recent study examined various summer programs implemented to promote healthy develop- References ment among school-age children and adolescents in order to determine the features that were Barbelivien A, Herbeaux K, Oberling P, Kelche C, important to demonstrate effectiveness (Bell and Galani R, Majchrzak M (2006) Environmental enrich- Carrillo 2007). While a number of specific fea- ment increases responding to contextual cues but decreases overall conditioned fear in the rat. Behav tures were identified, a general conclusion was Brain Res 169:231–238. that the instructional techniques were most effec- Bardo MT, Dwoskin LP (2004) Biological connection tive when academic learning was embedded in between novelty-seeking and drug-seeking motiva- enriching activities. These results suggest that tional systems. In: Bevins RA, Bardo MT (eds) Moti- vational factors in the etiology of drug abuse (The enrichment accelerates academic achievement Nebraska symposium on motivation). University of and promotes positive development. Nebraska Press, Lincoln, pp 127–158. E 620 Enzyme Induction

Bell SR, Carrillo N (2007) Characteristics of effective summer learning programs in practice. New Dir Epigenetics Youth Dev 114:45–63. Deehan GA Jr, Cain ME, Kiefer SW (2007) Differential 1 2 rearing conditions alter operant responding for ethanol Anthony R. Isles and Lawrence S. Wilkinson in outbred rats. Alcohol Clin Exp Res 31:1692–1698. 1Institute of Psychological Medicine and Clinical Del Arco A, Segovia G, Canales JJ, Garrido P, de Blas M, Neurosciences, and MRC Centre for Garcia-Verdugo JM, Mora F (2007) Environmental enrichment reduces the function of D1 dopamine Neuropsychiatric Genetics and Genomics, receptors in the prefrontal cortex of the rat. J Neural School of Medicine, Cardiff University, Transm 114:43–48. Cardiff, UK Rahman S, Bardo MT (2008) Environmental enrichment 2Behavioural Genetics Group, School of increases amphetamine-induced glutamate neurotransmission in the nucleus accumbens: a neurochemical Psychology and MRC Centre for Neuropsychiatric study. Brain Res 1197:40–46. Genetics and Genomics, School of Medicine, Raine A, Mellingen K, Liu J, Venables P, Mednick SA Cardiff University, Cardiff, UK (2003) Effects of environmental enrichment at ages 3–5 years on schizotypal personality and antisocial behavior at ages 17 and 23 years. Am J Psychiatry Synonyms 160:1627–1635. Renner MJ, Rosenzweig MR (1987) Enriched and impoverished environments: effects on brain and Chromatin remodeling; DNA marking behavior. Springer, New York. Stairs DJ, Klein ED, Bardo MT (2006) Effects of environmental enrichment on extinction and reinstatement of Definition amphetamine self-administration and sucrose- maintained responding. Behav Pharmacol 17:597–604. The development of the idea and the first use of Zhu J, Apparsundaram S, Bardo MT, Dwoskin LP (2005) Environmental enrichment decreases cell sur- the term “epigenotype” occurred as far back as face expression of the dopamine transporter in rat 1942 when Conrad H. Waddington suggested the medial prefrontal cortex. J Neurochem 93:1434–1443. existence of epigenetic mechanisms to explain the control of gene expression during cellular differentiation and maintenance of cellular identity. Implicit in the term epigenetics is that the mechanisms Enzyme Induction involved are labile (can be erased and reset), but also are heritable, in that they survive cell division. Definition However, as the techniques required to directly analyze these epigenetic mechanisms have been Process by which a molecule (e.g., a drug or developed and refined over the last two decades, it a hormone) induces the expression of an enzyme, is now recognized that these same molecular pro- mostly by stimulation of protein synthesis. cesses can play an important information-coding Depending upon the actions of the induced role in postmitotic tissues, such as those that occur enzyme, this may result in changes in the metab- in the brain. For the purposes of this review, epige- olism of other drugs or even that of the enzyme- netics can be loosely defined as the transmission inducing agent itself. and perpetuation of coding information that is not based on the alteration of the DNA sequence.

Enzyme Inhibition Principles and Role in Psychopharmacology Definition Mechanisms and Methods Inhibition of the catalytic activity of an enzyme The epigenetic code may be mediated via chem- by another molecule. ical marking of the DNA sequence itself (DNA Epigenetics 621 E methylation) and/or chemical tagging of histone represented on the array itself. The next- proteins that bind DNA and are molecular tools generation sequencing technologies are capable by which gene expression levels are controlled. of producing tens of millions of sequence reads DNA methylation represents the simplest epige- during each instrument run and identify any netic process, and usually, increased methylation stretch of DNA that is marked by a given epige- levels at gene loci equate to decreased expression netic modification effectively. Furthermore, of a gene. Most techniques to analyze DNA meth- ChIP-seq and MeDIP-seq offer other important ylation rely on bisulfite treatment of the DNA. advantages, including lower cost, minimal hands- Here, bisulfite effectively deaminates methylated on processing, and a requirement for fewer repli- cytosines to uracils, providing a difference that cate experiments, which are of great importance E can be detected by the direct assessment of the in the analysis of epigenetic changes in discrete treated DNA sequence. Recently, methylated brain regions, and less input material. DNA immunoprecipitation (MeDIP) techniques, whereby an anti-5-methylcytosine monoclonal Epigenetics and Neurodevelopment antibody is used to capture methylated genomic As originally suggested, epigenetic mechanisms DNA fragments, have allowed a more global are crucial in determining cell programming and, analysis of DNA methylation. consequently, development. Therefore, it is no Far more complex are the other epigenetic surprise that epigenetic processes are implicated mechanisms related to chromatin modification. in a number of neurodevelopmental disorders. Differing histone protein modifications result in Some of these, such as Rett syndrome (altered altered 3-D chromatin structures (open or DNA methylation and histone recruitment) and closed), meaning the DNA sequences underneath Rubinstein-Taybi syndrome (altered chromatin are more or less accessible to transcription binding protein), are caused by a disruption of an enzymes, which in turn leads to more or less epigenetic mechanism per se and consequently gene expression. Applying chromatin immuno- have greater effects on downstream genes through- precipitation (ChIP) techniques and utilizing out development. Others are due to less global recently developed antibodies that recognize spe- changes but are caused by the disruption of the cific histone modifications (acetylation, methyla- regulation of genes that are particularly sensitive to tion, phosphorylation, etc.) to appropriately variations in epigenetic control. Good examples of processed tissue preparations capture those these are Angelman (AS) and Prader-Willi (PWS) stretches of DNA bound by these modified chro- syndromes, which are caused by mutations of matin proteins. The relative abundance of a cluster of imprinted genes on Chr. 15q11-q13 a specific DNA sequence in a ChIP preparation that are particularly important for brain function allows the quantification of, for instance, Histone (Wilkinson et al. 2007). The imprinted genes are H3 acetylation at a given gene. However, unlike subject to tight epigenetic regulation that results in DNA methylation, the histone code is less easy to expression of these genes from one parental allele “read,” due to the many different types of histone (copy of gene) only; most genes are expressed proteins and possible modifications. from both the maternally and paternally inherited The analysis of both DNA methylation and copies. The expression of imprinted genes is chromatin modification is likely to greatly benefit controlled by a combination of differential DNA from the next-generation sequencing techniques methylation and histone recruitment to the paren- (Mardis 2007). Previously, the final analysis of tal chromosomes, and as a consequence, any ChIP and MeDIP experiments was either target disruption of these epigenetic processes leading driven, using quantitative PCR measurements of to an imbalance in the expression of these genes specific genes, or coupled to microarray technol- in turn results in abnormalities. ogies (ChIP-on-chip) for a more global analysis Many of these neurodevelopmental syndromes of which genes were epigenetically modified. are quite severe, often resulting in mental retarda- However, microarrays are limited by what is tion. However, there are also commonalities in E 622 Epigenetics terms of behavioral problems with other FosB gene promoter. The control of this change in non-syndromic psychiatric illnesses, in particular expression is due, in part, to a subtle switch in autistic-like symptomatology. These overlapping chromatin modification at the FosB promoter behavioral and cognitive problems may point to (Kumar et al. 2005). Acute exposure results a common underlying mechanism (Wilkinson in increased acetylation of Histone H4, but et al. 2007). This raises the possibility that more upon repeated exposure (and indeed self- subtle alterations in the epigenome may contribute administration), there is increased acetylation of to the vulnerability to mental illness, particularly Histone H3. Interestingly, it seems that the accu- when in combination with an existing genetic pre- mulation of DFosB also mediates the desensitiza- disposition (Isles and Wilkinson 2008). tion and epigenetic silencing of another Fos transcription factor, cFos, following repeated stim- Labile Epigenetic Mechanisms in the Brain ulant exposure (Pulipparacharuvil et al. 2008). Although many epigenetic modifications are devel- Taken together, these data indicate that chromatin opmentally determined, there is also an inherent remodeling is an important mechanism underlying lability in some, and these provide a molecular stimulant-induced neural and behavioral plasticity. mechanism by which environmental events may These techniques have now been applied to be integrated and translated into changes in the many other models of neuro- and psychopathol- control of gene expression. A striking example of ogy and indicated that epigenetic factors such as the epigenome’s ability to alter has recently been DNA methylation and chromatin remodeling shown by examining changes in DNA methylation may be important here too. These include the and histone modification at the genome level over regulation of neural changes related to learning time. In monozygotic twins, where the DNA code and memory (Miller and Sweatt 2007) and stress is identical, the epigenome of twins diverged with and depression (Tsankova et al. 2006). age (Fraga et al. 2005), suggesting that this may be a molecular mechanism by which differing life Advantages and Limitations experiences are encoded. The methods to examine DNA methylation and Although the idea of a role for epigenetic chromatin modification that have been developed modifications in neural processes was posited over the last decade or so allow us insight into the many years ago (Crick 1984), it is only very epigenetic control gene expression. Furthermore, recently that the tools and techniques have these techniques have provided evidence for become available to investigators. One key area a biochemical system which can encode life where the recently developed methods have been events – environmental pressures and stressors applied is in the study of molecular mechanisms being of particular importance to the vulnerabil- underlying drug addiction. Work in animal ity to psychiatric illness. However, in most cases, models has examined the epigenetic processes the existing techniques have been applied in ani- involved in regulating the changes in control of mal models, as, in the majority of cases, the expression of these genes by using behavioral availability of suitable samples limits clinical neuroscience techniques combined with DNA studies of epigenetic changes to surrogate tissues methylation and ChIP analysis on samples from such as blood, and unlike sequence information key regions of the brain. (i.e., genetics), the extent to which surrogate tis- The expression of the Fos (cFos, FosB) family sues tell us anything about epigenetic changes of transcription factors is correlated with the occurring in brain is, at best, uncertain. switch between acute and chronic cocaine expo- Additionally, although epigenetic mecha- sure. Upon first exposure, these are highly nisms are clearly of potential clinical relevance, expressed; however, expression becomes a key question is whether they are accessible to desensitized upon repeated cocaine dosing. Con- pharmacological intervention. There are versely, chronic exposure results in the accumula- a number of histone deacetylase (HDAC) inhibition of DFosB, an alternative transcript from the tors and DNA methyltransferase inhibitors that Episodic Memory 623 E are currently being used and/or tested as antican- ▶ Histone Deacetylase Inhibitors cer drugs. However, how applicable these are in ▶ Imprinted Genes potentially treating neuropsychiatric disorders is ▶ Learning and Memory: Molecular not clear – although valproate has HDAC inhib- Mechanisms itor properties and may, in part, exert its action ▶ Trichostatin A through epigenetic effects on the schizophrenia candidate gene Reelin (Guidotti et al. 2009). Cur- rently, a major problem exists between the spec- References ificity of the epigenetic changes that may occur in Crick F (1984) Memory and molecular turnover. Nature response to a given environmental or develop- E mental challenge in a specific population of 312:101 Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, brain cells and the relative nonspecificity of the Ballestar ML et al (2005) Epigenetic differences arise drug armory available to manipulate epigenetic during the lifetime of monozygotic twins. Proc Natl mechanisms. Essentially, at present this is limited Acad Sci U S A 102:10604–10609 to HDAC and DNA methyltransferase inhibitors. Guidotti A, Dong E, Kundakovic M, Satta R, Grayson DR, Costa E (2009) Characterization of the action of anti- Hence, experimentally, it can be difficult to prove psychotic subtypes on valproate-induced chromatin causal significance between a change in behavior, remodeling. Trends Pharmacol Sci 30(2):55–60 or some other aspect of brain function, and Isles AR, Wilkinson LS (2008) Epigenetics: what is it and a specific epigenetic change in a specific gene. why is it important to mental disease? Br Med Bull 85:35–45 Additionally, the current nonspecificity of the Kumar A, Choi KH, Renthal W, Tsankova NM, Theobald drugs available may limit therapeutic applica- DE, Truong HT et al (2005) Chromatin remodeling is tions due to unwanted side effects. What is a key mechanism underlying cocaine-induced plastic- urgently needed are more selective drug agents ity in striatum. Neuron 48:303–314 Mardis ER (2007) ChIP-seq: welcome to the new frontier. able to interfere with particular epigenetic modi- Nat Method 4:613–614 fications that can be targeted somehow to partic- Miller CA, Sweatt JD (2007) Covalent modification of ular genes. This would be a major step forward, DNA regulates memory formation. Neuron 53:857–869 not just for psychopharmacology, but for the use Pulipparacharuvil S, Renthal W, Hale CF, Taniguchi M, Xiao G, Kumar A et al (2008) Cocaine regulates MEF2 of such drugs across a wide range of other condi- to control synaptic and behavioral plasticity. Neuron tions, especially cancer. It is hoped that the ongo- 59:621–633 ing epigenome project (http://www.epigenome. Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, org/) and other initiatives, focused on the struc- Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antide- tural and allied medicinal chemistry (for instance, pressant action. Nat Neurosci 9:519–525 see http://www.sgc.ox.ac.uk/chemicalprobes/) Wilkinson LS, Davies W, Isles AR (2007) Genomic aspects of chromatin functioning, will provide imprinting effects on brain development and function. potential solutions to this limitation. Nat Rev Neurosci 8:832–843

Cross-References Episodic Memory

▶ Chromatin Definition ▶ Chromatin Immunoprecipitation ▶ DNA Methylation The capacity to mentally travel back in time to ▶ DNA Methyltransferase Inhibitors reexperience personal events. ▶ Gene Expression ▶ Gene Transcription ▶ Histone Cross-References ▶ Histone Acetyltransferases ▶ Histone Deacetylase ▶ Declarative and Nondeclarative Memory E 624 EPSPs and IPSPs

ligand-receptor complex dissociates into separate EPSPs and IPSPs reactants to the product of the reactants at equilibrium, KD = koff/kon = [L][R]/[LR]. Synonyms

Excitatory postsynaptic potentials; Inhibitory postsynaptic potentials Erectile Dysfunction

Definition Definition Erectile dysfunction is a sexual dysfunction char- An excitatory postsynaptic potential (EPSP) is acterized by the inability to develop or maintain the change in membrane voltage of an erection of the penis sufficient for satisfactory a postsynaptic cell following the influx of posi- sexual performance. There are various and often tively charged ions into a cell (typically Na+)as multiple underlying causes. The most important a result of the activation of ligand-sensitive chan- physiological causes include cardiovascular dis- nels. This results in a depolarization of the post- ease, diabetes, and drug side effects. Often psy- synaptic cell, thus increasing the likelihood of chological or relational problems are implicated action potential propagation. These excitatory as well. Besides treating the underlying causes synapses serve to increase excitability in and psychological consequences, the first-line neurones. Conversely, inhibitory postsynaptic treatment of erectile dysfunction is PDE5 inhibi- potentials (IPSPs) result from the influx of nega- tion by means of, for example, sildenafil tive ions (e.g., ClÀ) into, or the efflux of positive (Viagra), vardenafil (Levitra), or tadalafil ions (e.g., K+) out of, the postsynaptic cell. This (Cialis). results in cell hyperpolarization and thus decreases the likelihood of action potential propagation and therefore represent inhibitory synap- Cross-References ses. Both types of postsynaptic potential are graded and therefore sum together to have ▶ PDE5 Inhibitors a cumulative excitatory or inhibitory effect. ▶ Sildenafil

Cross-References Ergot ▶ Action Potentials Definition

Equilibrium Dissociation Constant Ergot is the general name for the sclerotia from any of the species of the fungus Claviceps that Synonyms infects grain crops. They produce the ergot alkaloids, mixtures of tetracyclic alkaloids that are

KD variously substituted at the C(8) position, typically with complex amide moieties. Ergot alkaloids are air and light sensitive and very toxic and Definition in earlier times were responsible for outbreaks of ergotism, or St. Anthony’s fire, where peripheral Reciprocal of affinity of a drug for a receptor. vasoconstriction could lead to gangrene and Equal to the ratio of the rate at which a necrosis of the fingers or toes, typically Estrogens 625 E accompanied by hallucinations and bizarre behavior. The most commonly used establishing behavior. Ergotism was caused by eating bread operations, often called deprivation, entail that had been made from ergot-contaminated restricting the previous availability of the rein- flour. The ergot alkaloids have served as the forcer. Establishing operations also temporarily starting materials for a number of valuable ther- increase the probability of behavior that has been apeutic agents such as ergonovine. Basic hydro- reinforced previously by the event/stimulus lysis of ergot alkaloids leads to production of whose reinforcing efficacy is increased. lysergic acid, the starting material for LSD.

E Estazolam Escitalopram Definition Synonyms Estazolam is a benzodiazepine derivative that Cipralex; Lexapro possesses anxiolytic, anticonvulsant, sedative, and skeletal muscle-relaxant properties. It is prescribed for the short-term treatment of certain Definition sleep disorders. It is an effective hypnotic drug showing efﬁcacy in increasing the time spent Escitalopram is a ▶ selective serotonin reuptake asleep as well as reducing awakenings during inhibitor (SSRI). It is commonly used in the treat- the night. Combination with nonpharmacological ment of depression and anxiety disorders (e.g., options for sleep management results in long- ▶ obsessive-compulsive disorder (OCD), panic term improvements in sleep quality after discon- disorder, social anxiety disorder, generalized tinuation of short-term estazolam therapy. There anxiety disorder). As with other ▶ SSRIs, the are concerns that estazolam may have abuse most troublesome side effect of escitalopram is potential when drug use is continued against sexual dysfunction (dysorgasmia and erectile medical advice. dysfunction); mild side effects include drowsi- ness, headache, and nausea. Escitalopram is the S-enantiomer of racemic ▶ citalopram, which is Cross-References also marketed as an antidepressant. ▶ Anxiolytics ▶ Benzodiazepines Cross-References

▶ Antidepressants ▶ Citalopram Estrogens ▶ Selective Serotonin Reuptake Inhibitors Synonyms

Oestrogens Establishing Operation

Definition Definition

Any operation that temporarily alters the effec- Estrogens are a class of hormones with tiveness of a consequence as a ▶ reinforcer of 17b-estradiol being the most potent estrogen E 626 Ethical Issues and the primary estrogen product of the ovary; centuries, in the last several decades, the use of other estrogens are metabolites of 17b-estradiol. animals for research has generated controversy. Researchers have dedicated their lives to developing life-saving treatments through the use of animals, yet groups of activists believe that ani- Ethical Issues mals are not our property or subject to our control and experimentation. Thus, consideration of eth- Definition ical issues is at the forefront of psychopharmacological research. This entry explores the ethical Ethical issues are a set of moral principles, relat- use of animals in terms of whether animals should ing to or affirming a specified group, field, or be used, how their use should be regulated, how form of conduct. their use has influenced psychopharmacological research, and what is the best animal to study. There are sources that have debated these ethical issues and provided examples of the ethical use of Ethical Issues in Animal animals in psychopharmacological research to Psychopharmacology promote the health of humans and other animals (e.g., Carroll and Overmier 2001). Marilyn E. Carroll1 and Peter A. Santi2 1Department of Psychiatry and Neuroscience, Ethical Considerations: Should Animals Be Medical School, University of Minnesota, Used? Minneapolis, MN, USA There have been several philosophers over the 2Department of Otolaryngology, University of last few centuries who have addressed the issue Minnesota, Minneapolis, SE, USA of the use of animals in research. The use of animals for research can be traced back to the seventeenth century with Rene´ Descartes, Synonyms a French philosopher/scientist (Descartes 1637). He established experimental methods for scien- Justifications for using animals; Morals and ani- tific investigation including his precepts: never mal use; Philosophical basis for using animals accept anything for true that is not clearly known to be such, divide difficulties into parts, analyze from simple to complex, and make complete Definition descriptions of your experiments. His work became the basis of the Cartesian coordinate sys- Justification for the care and use of animals in tem and the histogram. He also dissected live psychopharmacological research is based on animals and compared animals to machines with- philosophical arguments, moral principles, and out reason, soul, mind, or human intelligence. the consensus of reviewing boards and governing Descartes’ dualistic beliefs divided the body and agencies. mind into separate entities. In the eighteenth century, the German philosopher Immanuel Kant addressed the issue of Current Concepts and State of human rights and virtue (Kant 1785). He said Knowledge that animals do not have rights or duties. Moral rights are given and received by humans, not While the use of animals by humans for many among animals. Humans have obligations and purposes (e.g., food, labor, transportation) goes can make moral claims with other humans, but back to prehistoric times and the use of animals nonhuman animals do not have moral obligations for scientific research goes back several or rights. However, Kant recognized that animals Ethical Issues in Animal Psychopharmacology 627 E have feelings and needs and that humans have Adrian Morrison, a veterinarian and Professor a moral obligation to treat them well with human Emeritus from the University of Pennsylvania, dignity. has taught and written extensively on the Peter Singer is a utilitarian philosopher whose human–animal relationship. He has also endured book entitled Animal Liberation (Singer 1975) attacks from animal activists for his defense of ignited the animal liberation cause. Utilitarian- animal research. In his book, Morrison (2009) ism requires that a moral act should result in the points out the symbiotic nature of humans and greatest good (i.e., happiness) for the greatest nonhuman animals and the need for animal wel- number of people. Singer states that since humans fare laws that will maintain the health and well- and sentient animals can suffer, they are equally being of both humans and nonhuman animals. He E entitled to moral concern, and exclusion of ani- stresses that humans have a special obligation to mals from our moral concern is discriminatory provide excellent care for those animals under (which he calls speciesism). Singer does allow for their control (e.g., pets, farm, zoo, research). He animal research only if its benefits greatly out- explains that animals used in research are super- weigh the harm done to animals. However, the vised by veterinarians, protected by extensive question that remains is whether greater happi- legislation, and are housed and maintained by ness is the only thing that matters when determin- standards that far exceed any other form of ani- ing whether something is morally correct. mal husbandry. Thomas Regan (1985) is another philosopher who is concerned with the moral status of How Should Animals Be Used? nonhuman animals. He rejects the utilitarian The use of animals for research in the USA is claim on the basis of animals’ ability to suffer highly regulated by the Animal Welfare Act and states that nonhuman animals have rights (2006), the National Institutes of Health (NIH) simply because they have inherent value. He dis- regulations, Guide to Scientific Research, the agrees with Kant’s idea that moral rights should National Research Council, and rules of the edi- only be ascribed to humans. However, he admits torial boards of scientific journals. Before an ani- that when having to choose between a human and mal can be used in research by a qualified and an animal’s life, the human should take priority. trained scientist, the care and use of the animals Carl Cohen is a philosopher who returned to and the rationale for the research must be Kant’s ideas of moral rights for humans (Cohen approved by a local Institutional Care and Use 1986). He states that rights arise only among Committee (IACUC), and the work is monitored organisms (i.e., humans) who can make moral by the US Department of Agriculture (USDA). claims against one another. Animals cannot There are frequent inspections, in some cases respond to moral claims and they cannot evaluate unannounced (USDA), and follow-up visits if the conflict that may arise between their questions arise. IACUC applications must be self-interest and what is just. He believes that resubmitted and reviewed every 3 years. Animal we have obligations to animals to do no gratu- and research facilities must be maintained to itous harm (the principle of nonmaleficence) and extremely high standards and supervised by vet- to do good for animals within one’s power (the erinarians who require strict compliance with the principle of beneficence). He states that most NIH and USDA rules for the care and use of the people will agree that we should treat animals animals. In addition, the facilities that house ani- humanely, with decency and concern as sensitive mals are tested for temperature, humidity, and air human beings, but not as holders of human rights. quality and flow, and high standards are In addition, morality is a basis for many of our maintained. The NIH, major research centers laws, and when these laws are broken, a crime is (e.g., Sloan-Kettering Cancer Center, St. Jude’s committed. An animal cannot commit a crime Children’s Research Hospital, and the American because it does not understand morality or the Red Cross), and most large universities also have concept of being guilty. accreditation from a review board, such as the E 628 Ethical Issues in Animal Psychopharmacology

American Association for the Assessment and The second area is considered a subset of the Accreditation of Laboratory Animal Care first, but the problem (▶ Drugs of Abuse)isso (AAALAC), which reviews care, training, and immense that there are two other NIH institutes physical plant issues regarding the care and use that represent it: the National Institute on Drug of animals in research. Animal research facilities Abuse (NIDA) and the National Institute on have also become much more secure in recent Alcohol Abuse and Alcoholism (NIAAA). years, due to the attacks and destruction by Deaths due to drug abuse, particularly tobacco extremists. This prevents activists from releasing use, approach nearly half a million a year; thus, animals to a harmful environment and maintains understanding the etiology and neurobiology of the integrity of the research, but the downside is drug abuse and developing effective treatment that the high level of security distances the strategies is a national priority. Again, the abuse research from the general public that funds most of drugs begins at an early age and involves of the research and deserves to know about it. factors (genetic, developmental, and environmental) that are difficult to prospectively study The Use of Animals in and experimentally control in humans; thus, ani- Psychopharmacological Research mal models are essential to advance our knowl- There are two main areas in which animal models edge. As is the case with the first area, there are are used for psychopharmacological research. critical scientific approaches that can only be The first is to study the etiology and neurobiology done with animals, such as neurobiological that underlies psychiatric disorders affecting assays, embryonic and developmental studies, humans. Research on these disorders in the USA and neuroimaging (PET), which cannot be done is funded by the branch of the National Institutes with children under 18. of Health called the National Institute on Mental It is also important to study factors that influ- Health (NIMH) and by many other public and ence all phases of drug abuse, such as initiation, private organizations. The goal of these research maintenance, escalation (binging), withdrawal, institutes is to study brain disorders, some of and relapse, as in humans drug abuse is which develop early in life, such as attention a chronic relapsing disease. However, several of deficit hyperactivity disorder, eating disorders, these phases are difficult to study prospectively in drug dependence, mood disorders such as anxiety humans such as initiation and escalation or binge and depression, personality disorders (e.g., anti- use of the drug, as it is unethical to introduce social), schizophrenia, and those occurring later drugs to young teens or to encourage escalation in life such as Alzheimer’s disease and other of drug use in current users. Relapse is also diffi- forms of dementia. Animal models that are reli- cult to control and study in humans, as it would be able and have predictive validity have been unethical to promote the reinstatement of drug developed to represent many of the DSM use in abstinent individuals. While adult human (American Psychiatric Association 1994) diag- drug users can be studied in the laboratory, it is nostic criteria for substance abuse, and animal difficult to interpret the data because their histo- studies have identified the underlying causes of ries are varied and their self-report measures are these disorders and tested medications to treat unreliable. Furthermore, human subjects are not them. Since many of these conditions involve always compliant with instructions for medica- a gene, environment, development, interaction, tion use or nonuse of drugs of abuse prior to and neurobiological manipulations are necessary, laboratory visits. They are often not available they can only be conducted with animals, and for extended periods of time that are required to those results have been most informative for study the variables related to the study, and advancing the treatment of mental illness. Ani- absences are a problem for data collection. mal research has been crucial to the development The use of animals in drug abuse research has of many medications that allow mentally ill indi- led to our recognition of the main transition phases viduals to live normal, productive lives. associated with drug abuse (initiation, persistence, Ethical Issues in Animal Psychopharmacology 629 E escalation, and relapse), and the efficacy of phar- consumption), and their examination in animals macological and behavioral interventions may will be important for developing prevention strat- vary with phases of drug abuse (Carroll egies for humans. et al. 2009). Animal research has also informed us that individual factors such as age, sex, hor- What Animals Should Be Used? monal status, impulsivity, sweet preference, and As animals are used in the evolution of research in a proclivity for exercise predict vulnerability to psychopharmacology, more knowledge is gained drug abuse. Recent studies with animals that about the species that provides the best representa- have translated well to humans revealed the tion of human behavior, both with respect to under- behavioral economics of drug abuse that describe standing the disorder and to the effectiveness of E the compulsive nature of this disorder. Emerging treatment. Mice, for example, have been invaluable evidence from animal research has also connected for conducting gene knockout studies to elucidate many common behavioral and neurobiological the neurobiological bases of psychiatric disorders, features of drug addiction with excessive eating and genetically altered mice have shown remark- in animals and humans, and principles resulting able improvement in an animal model of from these animal studies will be useful Alzheimer’s disease. Rat studies have been useful in understanding and treating the obesity for developing animal models for depression, anx- epidemic. Rodent studies also identified environ- iety, drug abuse, and other disorders. Rat studies mental determinants such as stress and whether the also allow for group comparisons including individual is in an enriched versus impoverished dose–response analyses and control conditions. environment are also critically important to the Much of the behavioral pharmacological research development of drug abuse and the chronically that has been conducted in rodents has generalized relapsing nature of it. well to results obtained in NHP and humans. These vulnerability factors, which apply to A disadvantage of rodent studies is that in drug abuse and other psychiatric disorders, were some cases, pharmacological agents that are effi- primarily identified through the use of animals in cacious in rodents are not always translatable to research. With rats, it was possible to discover humans. For example, medications that prevent that the sex differences in drug abuse and related and reduce cocaine self-administration in rats disorders are accounted for by the ovarian hor- (e.g., fluoxetine) have not always been successful mones and to manipulate the hormonal milieu to for treating cocaine abuse in humans. It may be compare behavior over phases of the estrous a species difference in metabolism or pharmaco- cycle in rodents or the menstrual cycle in kinetics or the composition and distribution of nonhuman primates (NHP). Through selective receptors in rodent versus primate brains. NHP breeding in rat or selection of high and low models offer access to the genetic, environment, behavioral phenotypes in a large group of rats, it and early development interaction that leads to has been possible to relate sweet preference, the onset of mental illness in young adults. Psy- impulsive behavior, or a proclivity for exercise chopharmacological research in NHPs is closely for an avidity to self-administer drugs of abuse. translatable to humans, and there are several Adolescence is a critical period when vulnerabil- advantages of using NHP in this research; for ity to drug abuse is at its peak. We know that is example, NHPs have a similar, although con- true in humans, but is it cultural or developmen- densed, developmental period, hormonal cycle, tal/physiological? Animal studies have indicated and life span compared to humans. Their long life that in adolescence there is a confluence of hor- span (up to 40 years) allows for examination of monal surges, dietary influences, elevated impul- all ages and longitudinal studies. For drug abuse sivity, risk taking, reactivity to stress, and studies, NHPs are more amenable to being aggression in adolescents, and these factors trained to drink or smoke drugs, modes of drug explain the vulnerability of adolescents to drug use that represent the most common forms abuse and other addictive behavior (e.g., food of drug abuse in humans (Weerts et al. 2007). E 630 Ethical Issues in Animal Psychopharmacology

In contrast, rats are neophobic about drinking ▶ Animal Models for Psychiatric States drugs; thus, self-administration studies are typi- ▶ Anxiety: Animal Models cally limited to the i.v. route. ▶ Autism: Animal Models It is important for researchers who use animals ▶ Behavioral Economics to recognize when an animal species is a good ▶ Cocaine Dependence model for psychopharmacological research and ▶ Construct Validity when it is not, and the more animal models are ▶ Depression: Animal Models used, the more valuable feedback is provided about ▶ Eating Disorders: Animal Models their validity in terms of what aspects of psycho- ▶ Environmental Enrichment and Drug Action pharmacology can be successfully modeled in ▶ Face Validity humans. For example, factors developed using ▶ Genetically Modified Animals rodent research on relapse models have provided ▶ Impulse Control Disorders information about factors that trigger relapse and ▶ Intracranial Self-Stimulation treatments that prevent it in humans (e.g., naltrex- ▶ Open-Field Test one for alcohol abuse). In contrast, mice may not be ▶ Operant Behavior in Animals the best model for immunological research; testing ▶ Perinatal Exposure to Drugs the newly developed vaccines for cocaine, meth- ▶ Phenotyping of Behavioral Characteristics amphetamine, and nicotine may not be optimal in ▶ Predictive Validity mice. Thus, it is also important to recognize when ▶ Prepulse Inhibition we do not yet have a suitable animal model for the ▶ Primate Models of Cognition psychopharmacological research. ▶ Reinforcement Disorders In conclusion, ethical issues in animal ▶ Reinstatement of Drug Self-Administration research have been discussed for centuries; ani- ▶ Rodent Tests of Cognition mal research is considered legal and it is widely ▶ Schizophrenia: Animal Models used, but highly regulated. The US government ▶ Self-Administration of Drugs sanctions and supports animal research, contin- ▶ Sensitization to Drugs gent upon adherence to strict guidelines and mul- ▶ Sex Differences in Drug Effects tiple forms of oversight from national and local ▶ Sex Hormones boards. As a result of using animals over the last ▶ Social Stress several decades, animal research in psychophar- ▶ Stress: Influence on Relapse to Substance Use macology has made important advancements ▶ Translational Research in Drug Discovery in understanding underlying neurobiological ▶ Vaccines and Drug-Specific Antibodies mechanisms and in the development of psycho- ▶ Withdrawal Syndromes tropic medications for psychiatric disorders. Psy- chopharmacological research in the area of drug abuse has also gained important information from References animal research regarding the genetic, neurobiological, and behavioral precursors of drug abuse. American Psychiatric Association (1994) Diagnostic and statistical manual, 4th edn. American Psychiatric There are now successful treatments available for Association, Washington, DC the most common forms of drug abuse (alcohol Carroll ME, Overmier JB (eds) (2001) Animal research and tobacco use), and new treatments for and human health. American Psychological Associa- psychostimulant drug abuse are on the horizon. tion, Washington, DC Carroll ME, Anker JJ, Perry JL (2009) Modeling risk factors for nicotine and other drug abuse in the pre- Cross-References clinical laboratory. Drug Alcohol Depend 104(Suppl 1):S70–S78 ▶ Abuse Liability Evaluation Cohen C (1986) The case for the use of animals in bio- ▶ medical research. N Engl J Med 315:865–869 Addictive Disorder: Animal Models Descartes R (1637) Discours de la me´thode pour bien ▶ Aggression conduire sa raison, et chercher la verite´ dans les Ethical Issues in Human Psychopharmacology 631 E

sciences (trans: Ross GM 1998–1999). http://www. address questions about morality, such as what philosophy.leeds.ac.uk/GMR/hmp/texts/modern/des- nature of ethics or morality is (metaethics), how cartes/discourse/discourse.html. Accessed 11 Feb 2009 moral values should be established (normative Kant I (1785) Fundamental principles of the metaphysic of ethics), and how morals be attained in specific morals (trans: Abbott TK, Project Gutenberg EBook, situations (applied ethics). 2002). ftp://ibiblio.org/pub/docs/books/gutenberg/ The word ethics also refers to a system of etext04/ikfpm10.txt. Accessed 11 Feb 2009 Morrison AR (2009) An odyssey with animals. Oxford moral principles (i.e., the ethics of a culture) or University Press, New York rules of behavior assumed or mandatory in Regan T (1985) The case for animal rights. University of respect to a particular class of human actions or California Press, Ewing a particular group (i.e., bioethics, medical ethics). Singer P (1975) Animal liberation: a new ethics for our E treatment of animals. New York Review/Random House, New York Weerts EW, Fantegrossi WE, Goodwin AK (2007) The Current Concepts and State of value of nonhuman primates in drug abuse research. Knowledge Exp Clin Psychopharmacol 4:309–327 Psychopharmacology is an achievement of many players. The indispensable performers are the industry, which produces drugs; the researchers, Ethical Issues in Human who conceive new substances and test them; the Psychopharmacology administration, which gives the final approval to medicaments; the doctors, who prescribe them; Juan J. Lo´pez-Ibor1 and Maria-Ine´sLo´pez-Ibor2 and the patients, who take them. There are also 1Institute of Psychiatry and Mental Health, other secondary players such as the shareholders San Carlos Hospital, Complutense University, who expect profits from their investment, those Madrid, Spain who are involved continuous medical education 2Department of Psychiatry and Medical and policy makers at national and international Psychology, Complutense University, levels. Although the final goal may be common, Madrid, Spain namely, to improve the condition of patients and to increase the overall health, their values may be different and therefore conflicting (Jonsen 1988). Synonyms The ethics of medicine has three main sources that are often considered as stages in its devel- Ethics of placebo prescription; Ethics of opment although all of them are present nowa- prescription days: (1) the ethics of welfare, which are the traditional medical ethics. From this perspective, the duties of doctors are the well-being of Definition the patients and the harm to be avoided: (2) the ethics of autonomy, which considers that the The application of ethical issues to the develop- patient is an autonomous human being, adult, ment, research, production, approval, marketing, and free and able to take his or her own deci- and prescription of psychotropic drugs to be used sions. Consequently, doctors have to inform with human beings. patients about all possible diagnoses and treat- Ethics (from the Greek ethos “character”) is ments so that patients are able to decide and that branch of philosophy systematically study- (3) the ethics of equity, also known as the ethics ing the nature of values relating to human con- of management, which are the consequence of duct, with respect to the rightness and wrongness the impact of economic factors in medicine. of actions and to the goodness and badness of the From this perspective, the goal of health care is motives and ends of such actions. It seeks to the equal access to health-care resources for all E 632 Ethical Issues in Human Psychopharmacology patients and a larger level health care is only one hence potentially conflicting, value perspectives among several needs and rights of citizens. are in play. Values-Based Medicine is a response These three forms of ethics are present in to the growing complexity of the relevant values different proportions in the performers men- and it is a skills-based counterpart of the currently tioned above. As a result, the disagreement dominant quasi-legal form of clinical bioethics. among them is often profound and therefore the Quasi-legal ethics prescribes “good outcomes” in number of guidelines, recommendations, rules, the form of increasingly complex ethical rules consensus documents, and regulations is and regulations. Values-Based Medicine empha- overwhelming. sizes the importance of good process in the form These changes have had important and deep particularly of improved clinical practice skills. consequences for the way physicians take care of patients, although it has taken time to fully The Prescription of Psychotropic Drugs develop. Traditional medicine was based on Prescription of medicines is a basic aspect of a paternalistic ethics of welfare, where the doctor clinical practice, and it is the responsibility of took all the decisions and the patient was consid- every clinician, which cannot be handed over to ered as a minor. The paternalistic role of the anybody. The prescription should follow full doctor increased and achieved its highest expan- information from the doctor on the consequences, sion as medicine became more scientific because opportunities, and dangers of taking it, or of not his knowledge grew enormously and as taking it, and of the available alternatives. a consequence, his power to decide. However, This can lead to highly problematic situations, since the beginnings of the 1970s, the pressure such as that reflecting the obligation of informing of consumer associations in the United States led a depressed patient with suicidal ideation and to the rapid implementation of an ethics of intent about the possible greater lethality of a autonomy, in which the patient gained tricyclic antidepressant (TCA) than a selective protagonism in the decision-making process and serotonin reuptake inhibitor (SSRI). This might therefore the physician, instead of being the one lead the patient to favor the TCA precisely who decides, becomes the one who has to inform because of its greater lethality, which could facil- so that the patient can give his/her consent to the itate the patient’s suicidal intent. In spite of such different options. In the ethics of welfare, the difficulties, it seems that patients should know patient was initially the object of charity and that with some drugs the risk of death by poison- later on of scientific knowledge; in an ethics of ing is elevated and that other measures might be autonomy, the patient is a subject of rights. Now- needed to manage the risk of suicide. The issue adays, a new phase has emerged, the ethics of for the clinician is not lethality; it is suicidality. equity, because the physician is not any more the Confidentiality is an essential component of clinician in charge of a patient but a piece in a patient-doctor relationship and it includes the health-care structure that has to achieve increased prescription of drugs. levels of health for all citizens. The adequate Prescription is not an exclusive act in the frame- distribution and use of resources (material, work of the patient-doctor relationship, as all the human, and of time) is basic and therefore also partners mentioned above may interfere with it or the introduction of management procedures may have the right of some input or control over (Lo´pez-Munõz and Álamo-González 2007). it. Family members, the public and private health- It is not easy to deal with the conflicts of care administration, institutions, and even the legal values mentioned above, yet the perspective of system may claim a say on prescription. For that Values-Based Medicine (Fulford) can be very reason, it is the obligation of the doctor to maintain useful when faced with conflicts of interests and a level of professional formation and independent values. Values-Based Medicine is the theory and information, to allow him or her to make, at any practice of effective health-care decision-making moment, a rational, free, and ethical decision in the for situations in which legitimately different, and best interest of the patient. Ethical Issues in Human Psychopharmacology 633 E

The fact that psychiatric classifications since treatment on their own has changed the public 1980 rely on symptoms to make the diagnosis of perception and attitudes. Clinicians should be mental disorders has strong ethical implications aware that different values are in conflict in which are absent when dealing with diagnoses these situations, and that their duty is to try to based on objective anatomic pathology. establish an inspired doctor-patient relationship A psychiatric diagnosis is based on the presence and as a consequence to safeguard the dignity of of a number of criteria selected from a set. If the patients. number or the presence of some important Several studies show that a substantial number criteria are absent, then the patient may suffer of hospitalized chronic mental patients do not from a subsyndromal condition. Should it be have the capacity to appreciate the risks and the E treated? benefits of antipsychotic medication2 (Lo´pez- In most of cases, psychiatric symptoms are Ibor and Crespo Hervás 2000). also present in nonpsychiatric populations. Con- sequently, other secondary criteria have had to be Psychotropic Drugs and Stigma added, such as suffering and disability. Both suf- Like everything that has to do with mental illness, fering and disability are value-based concepts psychotropic drugs are often the object of stig- that are impossible to define scientifically. The matization, even from the semantic perspective. levels of suffering and disability can be manipu- Although in Spanish the words for “drug” and lated as well as the criteria for diagnosis, leaving “medicament” are different words, it sometimes the door open for possible abuses. happens that, by influence of English, these words are confused. In English, “drug” means, Informed Consent in Severe Psychiatric Cases simultaneously, drug and medicament. One of the There are differences in the legislation and prac- forms of stigma of mental illness is to deny its tice in different countries concerning the require- existence, to confuse it with psychological weak- ment of consent on the part of psychiatric nesses or with social processes of labeling and patients, depending on their level of mental exclusion. In this context, the need for psychotro- capacity. Some countries like the United King- pic drugs becomes an excuse or one more instru- dom have laws that authorize doctors to imple- ment of marginalization. It is not rare that ment treatment in such cases: the doctor must a person resists taking a psychotropic drug exert his power justly and exclusively in the because they think that they can overcome their best interests of the patient. In Spain the fact problems with sheer will, or because they do not that a patient is legally admitted does not auto- want to be considered a mental patient, or matically permits a prescription against the will because they fear that the drug can make them of the patient; therefore an informed consent less coherent, or because they do not want to should be looked for; if this is not possible, the become dependent on the drug or on the necessity clinician has to follow the rules of good clinical of treatment. “Well-intentioned” friends and practice and, above all, fulfill his duties as family often contribute to this attitude. a clinician. Other countries such as Italy are The psychotropic drugs are considered medi- very strict with long-acting antipsychotics with- cines that “drug up” the brain and that have unde- out the consent of the patient. The fact that com- sirable effects on sexual activity, metabolism or pulsory ambulatory treatment is becoming on one’s appearance. There is a perspective in possible in many countries is helping very much which the prescribing psychiatrist is seen as in difficult cases. A few decades ago, the impact a person who loves to impose their authority, of antipsychiatric propaganda and the stigma of destroying the liberties of the patient. Poorly mental disorders prevented such kinds of forced trained doctors contribute to this attitude, as can prescriptions. Yet, the importance given in the pharmacists who, with the excuse of some inter- media to tragic cases of homicides by untreated vening disease or treatment, decide that the best psychiatric patient or by those who interpreted thing for the patient is to interrupt the treatment E 634 Ethical Issues in Human Psychopharmacology with the psychotropic medication. This can placebo, and not only in psychiatric settings. further result in a situation in which, after the Sometimes, clinical use of placebos is due to the discontinuation of an antipsychotic or antidepres- lack of an effective treatment for a specific dis- sant, replacement treatment is instituted with ease, but in others, it is simply to be freed of the an inappropriate alternative, such as a pressure of the patient and their relatives benzodiazepine. (Emanuel and Miller 2001). Independently of More recently, the cost of second-generation the cost of such practices, placebo prescription (atypical) antipsychotics. has resulted in these outside of research protocols is a violation of the agents coming under attack. The argument is doctor-patient relationship. A doctor acting as made that their price is excessive, and policies such can only behave as a doctor. The Madrid favoring the use of the first-generation (typical) Declaration is clear about this. If circumstances antipsychotics {classic neuroleptics) have been force him or her to take decisions that a clinician proposed, as they are much cheaper when one should not undertake, he or she could neverthe- solely examines the unit price. However, most less proceed with them in order to prevent impor- of the serious studies of pharmacoeconomics tant harms, but with the clear knowledge that this that include data on suicides, suicide attempts, may be the end of the doctor-patient relationship. assistance, and disability demonstrate that the This assessment reflects court expert witness dec- classic neuroleptics are not advantaged in this larations. Placebo prescription falls within this sense. This coincides with the fact that although perspective, with the added consideration that the cost of mental and cerebral diseases is, in misuse of the authority to prescribe constitutes general, very high, the resources devoted to one of the most serious violations of ethically them are small. Studies by the European Brain acceptable practice. Council indicate that, despite the high cost of brain disorders, only 8 % of the research funds The Misuses of Psychotropic Drugs in biomedical sciences and 5 % of the financing In the English language the word drug refers both of the Framework Program are committed to to a medicine and to a poison, and the same these disorders. Altogether, 0.001 % of the happens in ancient Greek with the word Gross Internal Product (GIP) is invested in pharmakos. In other languages, the word drug is research in brain disorders. reserved for illicit substances, but still the cutting Psychotropic drugs can also contribute to the edge between both meanings is far from clear. stigmatization of mental illness as a result of their For instance, there are restrictions on the pre- side effects. For example, the extrapyramidal side scription of benzodiazepines because of the effects of first-generation antipsychotics can give potential risk of dependence, although the restric- the patient the appearance of an elderly person tion criteria are not the consequence of scientific with Parkinson’s disease. Additionally, there are evidence. Why is there a 2-month limit and not a metabolic effects, especially obesity, and sexual 2-week or a 6-month one? The case of white effects, such as impotence and loss of sexual blood cell monitoring with clozapine use is desire. Nevertheless, the psychotropic drugs can another example. The evidence is that the danger also contribute to the destigmatization of mental for a severe leucopenia becomes minimal after illnesses: in the first place, because they offer a few weeks of intake. Every country has a huge possibilities for treatment, and secondly, because database of patients on clozapine and weekly or the development of drugs with a better side effect monthly white blood cell, and nobody has had the profile can result in patients feeling less stigma- courage to analyze these databases to produce tized and that their disease is less noticeable. clear guidelines on the controls needed to monitor such a drug or other drugs which may share The Ethics of Placebo Prescription the same risk. The term “drug” conveys a magical element, Cosmetic psychopharmacology refers to the which is clearly manifested in the power of the use of psychotropic medication by people who Ethical Issues in Human Psychopharmacology 635 E are not ill but intend to enhance well-being and healthy people might receive a psychiatric diag- functioning. A futile prescription is something nosis in order to get a prescription or that diag- different, because this is a medical intervention nostic criteria might become less restrictive. which has no value for the patient (who may be severely ill), although it will produce some effect. The Development of New Medicines for the Cosmetic or palliative pharmacotherapy is to Health-Care Market use a psychotropic agent to make a person who is The development of new medicines has gener- not ill feel better. It usually intends to mitigate ated ethical problems that have been dealt with by unwanted or unaccepted psychological traits in legal norms and strict regulations. order to attain a higher order of social normality In spite of the fact that modern pharmacology E and acceptability. The issue was raised by has contributed to a better quality of life for Kramer (1993) who described how fluoxetine many patients all over the world, the issue of used for the treatment of depression and for the advantages of new (and expensive) drugs other psychiatric disorders was able to eradicate versus older (and cheaper) ones is today a hot some personality traits also present. He observed one. This is a typical case of conflict of values that such traits had previously been considered as between doctors on one side and the health-care an expression of human miseries or, in some authorities on the other. Doctors are guided by cases, as the consequence of negative childhood the ethical principles of welfare, and therefore experiences. Kramer even questions whether any medicament that may bring a benefit to there could be a “pandemic” of cosmetic psycho- a patient, even a minor one, should be pre- pharmacology which would lead to the disap- scribed. Health-care administrators, working on pearance of phenomena such as anguish which tight budgets that are constrained by yearly allo- are essential for personal realization in the arts, cations and by the decisions of higher authori- religion, and creativity. ties, follow the principles of the ethics of Cosmetic and plastic surgery is more often management. In the case of psychiatry, the than not carried out people who do not fulfil stigma of mental disease and of psychiatry itself criteria for any disease. The interventions in this plays a major role in this context. area are not always necessary from the clinical Pharmacoeconomic studies cannot rely exclu- point of view. But in the cases of some psychiat- sively on the daily cost of the medication, but ric disorders, the situation is different. they must also include direct costs Healthy persons that are unhappy with their (hospitalization and use of the health-care ser- own personality traits because they may not be vices, treatment of adverse effects and overdoses, socially acceptable may turn their eyes to cos- home care, psychosocial interventions, etc.), metic psychopharmacology to achieve a more indirect costs (absenteeism, social issues, etc.) satisfactory level of normality. The fact is that and intangible costs, such as suffering, disability psychotropic drugs can produce such benefits: for the patient and the relatives, and the patient’s fluoxetine allows feeling energetic, bright, and quality of life, as well as costs of planning and accepted; beta blockers and paroxetine can management (suicide prevention programs, anti- change the life of shy people and improve the stigma interventions, etc.). performance of artists who suffer from stage Defensive medicine is not only a matter of fright. This last use has been considered as doctors or hospitals but also an issue of the a form of doping. There is also an increasing use health-care administration, as the clozapine case of cognitive enhancers to improve performance shows. and endurance, commonly by students and people in intellectually very competitive jobs, although The Ethics of the Marketing Psychotropic the evidence of their usefulness is very scarce. Drugs As in the case of cosmetic surgery, the inter- The ethical problems of psychotropic drugs do vention needs a doctor, and there is the risk that not disappear when the drug is marketed. E 636 Ethical Issues in Human Psychopharmacology

Even when a medicine has been approved and aiming to curb abuses in this field (World Psy- commercialized, ethical problems in its prescrip- chiatric Association 1996). The same aims are tion can appear. The quality of marketed medica- regulated in the European Union. tions is assured by the proceedings and The fact that there is something wrong in this exigencies imposed by the health-care system field was clearly exposed by Palmisano and that guarantee the drug as a remedy Edelstein in the United States. They compared (effectiveness) and in addition delimit the possi- the expenses in medicine promotion by the phar- ble adverse effects (safety). The guarantees maceutical industry during the 1970s with the address use in specified indications, based on expenses on health care for young people by the the research presented for the approval. Yet, it health authorities. The results were overwhelm- should be clear that the goal of this process is to ing: $3,000 per doctor per year in medicine pro- assure that the drug has potential effects on some motion, as opposed to $212 per person per year in disease or syndrome and the level of potential health care. side effects is within acceptable limits. The rest, how the drug compares with others, what is its Research niche within the therapeutic armamentarium, Research, in general, and clinical research, in what are the benefits in populations not previ- particular, plays a significant although indirect ously exposed to the drug (children, elderly role in the act of the prescription, filtered by patients, patients with comorbid conditions, and measures imposed by regulating authorities, so on), the benefits in other disorders or in sub- information conveyed by the pharmaceutical threshold conditions, is another story. industry and by continuous medical education The pharmaceutical industry considers itself activities, often promoted by the pharmaceutical as an essential element of health care and proba- industry. In addition, the publishing of clinical bly more than other sectors it has recognized research in scientific publications is greater every ethical issues. In any case, it is a highly regulated day. Nevertheless, from an ethical perspective, industry, contrary to what happens with some the financial support of these means of diffusion other medical interventions. on the part of the pharmaceutical companies is Several ethical problems exist in the area of problematic, although societies or scientific com- marketing of drugs to health care professionals: mittees of an independent nature guarantee their (1) gifts offered to health professionals, where content. there is consensus that they must be of little Other biases that can change the prescription value and be related to the practice of medicine habits for psychotropic drugs are the influence or pharmacy; (2) hospitality in professional exerted by the so-called “opinion leaders.” meetings, which should not include “congress Another aspect is “ghost writing,” which means tourism” activities; (3) the quality of all the that a scientific paper may have been written by advertising material, which should be prepared pharmaceutical company employees or by spe- by the scientific departments of pharmaceutical cial firms engaged in the business of writing companies and duly supervised by health-care scientific papers and reports and not by authorities. David Healy (Healy 1991) has called researchers involved in the actual investigation. attention to some marketing campaigns and In a meeting of the Permanent Committee of strategies that were deprived of sufficient scien- Doctors of the European Community, they rec- tific support. The World Psychiatric Association ognized the problems caused by the rapid has included an item on the ethical implications increase of health-care costs and acknowledged of the relationship of psychiatrists with industry that this concerns not only governments and cit- as a part of the Madrid Declaration, and most of izens but also the medical profession. However, the national and international organizations in they concluded, unanimously, that it is “the duty the field of neuropsychopharmacology or psy- of the doctor to oppose all measures that, destined chiatry have produced ethical recommendations to control expenses, violate medical ethics.” Ethical Issues in Human Psychopharmacology 637 E

In addition, they mentioned in the document that that follows the Hippocratic principle primum “the health sector not only is an expense, but also non nocere and puts particular emphasis on a benefit for the state and for public health, and, obtaining the person’s voluntary consent. therefore, it is correct to consider it from an The ethical and scientific models for economically positive point of view and not conducting biomedical research on humans have only in terms of expenses.” Yet, on the other been developed through various international hand, without health-care services supported by guidelines: the Declaration of Helsinki (1964) the administration, only wealthy patients could and its subsequent amendments (Tokyo 1975; afford what a doctor prescribes, and without Venice 1983; Hong Kong 1989, Somerset West question, the number of jobs for doctors would 1996; Edinburgh 2000) of the World Medical E be very much reduced. Association (WMA), the International Ethical The use of placebo in clinical research raises Guidelines of the Council for International Orga- major ethical problems. In a strict sense the use of nizations of Medical Sciences (CIOMS), and the placebo in clinical trials could be considered as International Conference of Harmonization being against the spirit of the Helsinki Declaration. (ICH) guides for good clinical practice (GCP), But on the other hand treatment is not just the which are at the core of most national and inter- prescription of a drug. Treatment is the result of national legal standards on medical research pharmacological effects and of the doctor-patient involving human subjects. interaction. In psychotherapeutic research novel The Nuremberg Code, the Declaration of Hel- approaches are compared with “treatment as sinki, and the ICH Guides have led to GCP, an usual” interventions. The challenge is to design international standard of ethics and scientific studies where the more or less nonspecific role of quality for the design, implementation, records, the doctor-patient relationship and the treatment as and reports on investigations involving humans. usual approach are as controlled as the effects of Later on, the United Nations and World Psy- the drug being tested. The fact is that in the par- chiatric Association (1996) produced codes spe- ticular case of psychopharmacology, there is cifically oriented to psychiatry and the care of a high placebo response rate in many psychiatric mental patients (Resolution 211, Hawaii Decla- disorders. ration 1977; Madrid Declaration 1996).

Patients as Research Subjects Publications and the Dissemination of the Although Claude Bernard declared in 1874 that Results of Research “the principle of medical morality is to never The publication and the dissemination of the perform an experiment on a human being that results of research projects is a major ethical may be harmful to some extent, although it may concern. The selective publication of clinical tri- be very beneficial to science, namely for the als distorts the body of evidence available for health of others,” this principle was repeatedly clinical decision-making. Thus, researchers and violated and in an extreme form in Germany editors are often more enthusiastic about the pub- during the Third Reich. The fact is that doctors lication of studies that show a very significant at least passively accepted laws put forward by effect of a new treatment (positive test) or an the Nazi regime declaring that such regulations equivalence between two therapeutic approaches were designed to benefit the nation and not the (non-inferiority trials). On the contrary, patient, an example of conflict of values. Nowa- researchers and editors tend to show little interest days the Madrid Declaration of the World Psy- in trials that show that a new treatment is less chiatric Association clearly affirms the effective than the standardized treatment for independence of psychiatrists and their right to a specific disease (negative trials), let alone practice their profession free from external pres- those that are not clearly positive or negative, sures. The first international code of ethics for because inconclusive studies do not change rou- research on human beings is the Nuremberg Code tine clinical practice. E 638 Ethics of Autonomy

The editors of several major medical journals Daly RJ (1994) Medico-legal aspects of prescribing. Hum have demanded greater transparency in the Psychopharmacol 9:S31–S36 Directive of the Council of the European Union 92/28/ implementation and publication of clinical trials, CEE, March 31, 1993 requiring, as a prerequisite for dissemination, the Emanuel E, Miller F (2001) The ethics of placebo- registration of the trial in a public database. controlled trials. A middle ground. N Engl J Med Yet the publishing business is not free of 345:915–919 Guidelines for Good Clinical Practice. ICH Harmonised unethical behavior, and there is a risk that the Tripartite Guideline. International Conference on danger may increase in the future. Scientific Harmonisation of technical requirements for journals with high impact factors are major registratkion on pharmaceuticals for human use 1996 players in research, as the investigator’s career Healy D (1991) The ethics of psychopharmacology. Changes 9:234–247 stands on his or her published output. Therefore, Jonsen AR (1988) Ethics of drug giving and drug taking. the policies or even ideologies of a journal can J Drug Issues 18:195–200 have an indirect influence on grants accorded to Kramer PD (1993) Listening to Prozac. Viking, New York investigators. This may even be present in edito- Lo´pez-Ibor JJ Jr, Crespo Hervás MD (2000) A West Med- iterranean perspective. In: Okasha A, Arboleda-Florez rials: the publication of a paper on the compari- J, Sartorius N (eds) Ethics, culture and psychiatry. son of typical and atypical antipsychotics, which International perspectives. American Psychiatric showed favorable results for the latter based on Press, Washington, DC retention rates, was accompanied by an editorial Lo´pez-Munõz F, Álamo-González C (2007) Historia de la Psicofarmacologıá, vol III, La consolidaciońdela which only commented that there were not dif- psicofarmacologıá como disciplina cientı´fica. ferences in the scores on the Positive and Nega- E´ tica en psicofarmacologıá. Editorial Me´dica tive Syndrome Scale (PANSS), withholding that Panamericana, Madrid this was a secondary outcome measure and the World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human study was not powered to find differences in the subjects: adopted by the 18th WMA General Assem- clinical scales. The issue becomes more impor- bly (Helsinki, Finland, June 1964), and amended by tant as some journals are now considering them- the 29th WMA General Assembly (Tokyo, Japan, selves as major players in the health care sector, October 1975), the 35th WMA General Assembly (Venice, Italy, October 1983), the 41st WMA General assuming the power to correct injustices around Assembly (Hong Kong, September 1989), the 48th the world. WMA General Assembly (Somerset West, Republic of South Africa, October 1996), and the 52nd WMA General Assembly (Edinburgh, Scotland, October 2000). WMA, Ferney-Voltaire. http://www.wma.net. Cross-References Accessed 31 Aug 2009 World Psychiatric Association (1996) Declaration of Madrid. X World Congress of Psychiatry, Madrid ▶ Legal Aspects of Psychopharmacology ▶ Licensing and Regulation of Medicines in the UK ▶ Neuroethics ▶ Pharmaceutical Cognitive Enhancers: Ethics of Autonomy Neuroscience and Society Definition

References The ethics of autonomy considers that the patient is an autonomous human being: adult, free, and Council International Organizations of Medical Sciences able to take his or her own decisions. Conse- (CIOMS) in collaborations with the World Health quently, doctors have to inform patients about Organization (WHO) (1993) International ethical guidelines for biomedical research involving human all possible diagnoses and treatments so that subjects. WHO, Geneva patients are able to decide. Ethopharmacology 639 E

the behavioral repertoire and the environmental Ethopharmacology circumstances (antecedent, concurrent, and consequential) in which it is found, systemic Berend Olivier alteration of environmental conditions, includ- Department of Psychopharmacology, Utrecht ing the administration of a drug, can be University, Utrecht, The Netherlands undertaken. Krsˇiak (1991) defined ethopharmacology as “the study of behavioral and other effects of Synonyms drugs through the application of ethological concepts” in an article describing the historical E Ethological pharmacology; Pharmaco-ethology contexts of the field. In his view, ethopharmacology is a subspecialty of the broader field of behavioral pharmacology, which reflects the Definition behavioral effects of drugs on species by all kind of methods. Ethopharmacology can be described as the study The first “ethopharmacological” studies were of drug effects on behavior, relying on observa- performed in the early 1960s by scientists tions and descriptions of species-specific ele- (Chance and coworkers) coming from an etho- ments (acts and postures). It is therefore logical background. This group did most of their strongly rooted in principles derived from ethol- groundbreaking work on social behavior in ogy, a biological approach to the study of animal rodents and they were the first to describe and human behavior. The roots of ethology lie in ethograms of isolated behaviors and social inter- evolutionary biology as defined by Darwin actions (Grant and Mackintosh 1963). An and others and, more specifically, by the studies ethogram is a list of all acts and postures of an of Lorenz, Tinbergen, and Von Frisch. Of cen- animal in a certain environmental situation. tral concern in ethology are the functional Ethopharmacology has particularly blossomed aspects of behavior and its adaptive value in in the area of social interactions and aggression evolutionary terms where it contributes along research probably due to the availability of with genetic and environmental factors to natu- ethologically trained scientists, the rich agonistic ral selection. repertoire of rodents, and the translational aspects of such research into human biomedical (psychiatric) problems (Miczek et al. 1994). Current Concepts and State of The ethopharmacological approach is Knowledge illustrated here in the area of aggression or agonistic behavior. Before the 1960s, the effects Ethologically based behavioral models, thereof drugs were assessed in very simple aggression fore, tend to focus upon a species’ entire behav- tests often measuring only one parameter (e.g., ioral repertoire, which is divided into clearly the number of bites, Yen et al. 1959). Such identifiable units of behavior (acts and postures, parameters did not unravel whether a drug was e.g., eating, grooming, walking, exploring, and selectively antiaggressive or just sedative. There- fleeing). The repertoire is defined in naturalistic fore, ethological approaches were introduced to settings by comprehensive, systematic observa- better describe and interpret the effects of drugs tion and recording of the species’ behavior on behavior. Agonistic behavior, as found in (including gender and age-related differences) a variety of animal models, includes a number without resort to a priori theories or hypotheses of behavioral components with complex func- which putatively might bias the objectivity of tions that have been organized in certain patterns the observation. Having exhaustively defined and sequences. The species-specific behavioral E 640 Ethosuximide patterns, taken together, can be considered the in describing the basal effects of these drugs on species’ agonistic behavioral repertoire. The various aspects of agonistic behavior. diversity of the repertoire, that is, the number and subtlety of behavioral options available, is smaller in more primitive species and becomes References apparently larger and more complex in the higher orders. Investigators try to use “models” of ago- Grant EC, Mackintosh JH (1963) A comparison of the nistic behavior and mostly this is done in rodents. social postures of some common laboratory rodents. Behaviour 21:246–259 Depending upon the model used, as defined by Krsˇiak M (1991) Ethopharmacology: a historical perspec- the specific environmental situation constructed, tive. Neurosci Biobehav Rev 15:439–445 a particular frequent and temporal distribution of Miczek KA, Haney M, Tidey J, Vatne T, Weerts E, the species’ behavioral repertoire can be elicited. DeBold JF (1989) Temporal and sequential patterns of agonistic behavior: effects of alcohol, anxiolytics In a territorial (resident-intruder paradigm) and psychomotor stimulants. Psychopharmacology model of agonistic behavior in rats, the resident (Berl) 97:149–151 male ordinarily takes the offensive role and the Miczek KA, Weerts E, Haney M, Tidey J (1994) intruder, a defensive role. Although both rats Neurobiological mechanisms controlling aggression: preclinical developments for pharmacotherapeutic have available identical behavioral repertoires, interventions. Neurosci Biobehav Rev 18:97–110 the two rats show a completely different fre- Mos J, Olivier B, Van der Poel AM (1987) Modulatory quency, sequence, and temporal distribution of actions of benzodiazepine receptor ligands in agonistic behavioral elements. On the basis of these behaviour. Physiol Behav 41:265–278 Olivier B (1981) Selective anti-aggressive properties of different distributions, the overall behavior of DU 27725: ethological analyses of intermale and ter- each contributor can be classified as either ritorial aggression in the rat. Pharmacol Biochem offensive or defensive. The ethopharmacological Behav 14:61–77 approach has been used in developing Olivier B, Van Daalen D (1982) Social behaviour in rats and mice: an ethologically based model for differentiating specific antiaggressive drugs, serenics (Olivier psychoactive drugs. Aggress Behav 8:163–168 et al. 1984, 1990a, b). These compounds have Olivier B, Van Aken H, Jaarsma I, Van Oorschot R, highly selective effects on offensive components Zethof T, Bradford LD (1984) Behavioural effects of of agonistic behavior while not influencing psychoactive drugs on agonistic behaviour of male territorial rats (resident-intruder paradigm). In: Miczek KA, defense and flight. Using extensive ethograms Kruk MR, Olivie B, Alan R (eds) Ethopharmacological (Olivier 1981) and describing drug effects on aggression research. Liss, Inc., New York, pp 137–156 frequency and time distributions on the sequen- Olivier B, Rasmussen D, Raghoebar M, Mos J (1990a) tial structure and the timing of behavioral ele- Ethopharmacology: a creative approach to identification and characterisation of novel psychotropics. Rev ments enabled the very precise and Drug Metab Drug Interact 8:11–29 sophisticated development of antiaggressive Olivier B, Mos J, Rasmussen D (1990b) Behavioural drugs, where effects on offensive behaviors pharmacology of the serenic eltoprazine. Rev Drug could be distinguished from sedative, sensory, Metab Drug Interact 8:31–83 Olivier B, Mos J, Raghoebar M, de Koning P, Mak M or motor deficits or interfering other behaviors (1994) Serenics. Prog Drug Res 42:167–308 (Miczek et al. 1989; Mos et al. 1987; Olivier and Yen CY, Stanger RL, Millnam N (1959) Ataractic sup- Van Daalen 1982). By testing an extensive bat- pression of isolation-induced aggressive behavior. tery of drugs from various classes (anxiolytics, Arch Int Pharmacodyn Ther 123:179–185 antidepressants, antipsychotics, anticonvulsants) in different agonistic models, including maternal aggression in female rats, territorial aggression in Ethosuximide male rats and mice, brain-stimulation-induced aggression, and others (cf. Olivier et al. 1994), Definition and using the ethological approach, an extensive and subtle profile of these psychotropics could be Ethosuximide is an antiepileptic drug, used nota- generated that appeared to be extremely helpful bly in treating absence seizures that are EUFEST 641 E characterized by lapses of consciousness/staring amnesic, and muscle-relaxant properties. that usually only lasts a few seconds. It is used for short-term treatment of ▶ insom- nia, ▶ anxiety,and▶ panic attacks.Alpha- hydroxyetizolam is an active metabolite that is Cross-References eliminated more slowly with a half-life of 8 h. Etizolam differs from other benzodiazepines in ▶ Anticonvulsants that the molecules possess a thiophene ring instead of a benzene ring. Cases of increased prolactin and ▶ neuroleptic malignant syndrome, which are typically reported for neuro- E Ethyl Loflazepate leptics and not for benzodiazepines, have been reported with etizolam. Definition

Ethyl loflazepate is a benzodiazepine that has Cross-References anxiolytic, anticonvulsant, sedative, and skeletal muscle-relaxant properties. It is used for the treat- ▶ Anxiolytics ment of anxiety, posttrauma anxiety, anxiety ▶ Benzodiazepines associated with severe neuropathic pain, ▶ generalized anxiety disorder, and ▶ delirium tremens. Its ▶ elimination half-life is 51–103 h. It is mainly metabolized by cytochrome P450 3A4 and produces an active metabolite that is EUFEST more potent than the parent compound. The symptoms of an overdose of ethyl loflazepate Synonyms include sleepiness, agitation, and ataxia. Hypoto- nia may also occur in severe cases. These symp- The European Union First Episode Schizophre- toms occur much more frequently and severely in nia Trial; Effectiveness of antipsychotic drugs in children. High doses of the antidepressant first episode schizophrenia and schizophreniform ▶ fluvoxamine may potentiate the adverse effects disorder study of ethyl loflazepate. Like most similar compounds, it is subject to dependence and abuse. Definition Cross-References An open, randomized clinical trial of a low dose of haloperidol (1-4 mg) versus SGA in ▶ Abuse first-episode schizophrenia. This pragmatic trial ▶ Benzodiazepines found lower discontinuation rate with SGA than ▶ Dependence with haloperidol. However, symptom reductions ▶ Fluvoxamine were virtually the same in all the groups, at around 60 %.

Etizolam Cross-References Definition ▶ Haloperidol Etizolam is a benzodiazepine that has ▶ Schizophrenia anxiolytic, anticonvulsant, hypnotic, sedative, ▶ Second-Generation Antipsychotics E 642 Event-Related Potential

to the event of interest and isolates the ERP – the Event-Related Potential systematic response of the EEG to the event (Luck 2005). Sander Nieuwenhuis and Mischa De Rover Cognitive Psychology Unit, Institute of Properties of ERP Components Psychology, Leiden University, Leiden, ERPs consist of a series of peaks and troughs that AK, The Netherlands are referred to as ERP components (Fig. 1a). The naming of these components often reflects their polarity (P for positive, N for negative voltage) Synonyms and their order of occurrence (e.g., P1 is usually the first negative component) or typical timing in ERPs milliseconds after the event (e.g., P300). Apart from their polarity and latency, ERP components can be characterized in terms of their general Definition scalp distribution (Fig. 1b). The relationship between the voltage distribution observed over Event-related potentials are a general class of the scalp and the brain regions giving rise to this electrical brain potentials that are embedded in pattern is by no means transparent. This is the electroencephalogram and that display because there is, in principle, an infinite number a stable time relationship to a definable sensory, of cortical source configurations that can produce cognitive, or motor event. the same scalp distribution – a methodological problem known as the inverse problem. Nonethe- less, the scalp distribution can be used to infer or Principles and Role in test coarse hypotheses about a rather localized Psychopharmacology neuronal population or multiple, anatomically distributed populations that generate an ERP Electroencephalography is one of the most pop- component. This can be achieved using source ular psychophysiological methods in clinical and localization techniques, which limit the number preclinical research and provides a recording that of possible source configurations by making sim- reflects the global electrical activity of the plifying assumptions about the physics of the brain – the EEG. A limitation of the EEG is that brain and head tissues, as well as the nature of it represents the summation of all the electrical the active neuronal populations (Handy 2005; activity at a given moment in time, making it Luck 2005). difficult to isolate the activity associated with One must exercise great caution when using individual neurocognitive processes. A more ERP component measures for drawing conclu- powerful method for the study of isolated sions about underlying neural processes. One dif- neurocognitive processes focuses on the specific ficulty is that ERP components can reflect the EEG responses to particular sensory, cognitive, combined activity of multiple, relatively inde- or motor events. Such specific responses are pendent, underlying or latent components that called event-related potentials (ERPs), to denote are overlapping in time and/or location. In that the fact that they are associated with specific case, the neural process of interest typically cor- events. The ERP is difficult to see in the EEG responds with only one of those latent compo- recorded for a single event. To isolate an ERP, nents. Furthermore, differences between one must collect the EEG of a large number of experimental conditions or groups in the scalp trials with the event of interest, time-lock the distribution of a component need not necessarily corresponding signals to the onset of this event, represent the involvement of different neural and then average the signals. The averaging pro- sources but may also reflect different relative cess filters out all EEG activity that is not related contributions of the same sources. Techniques Event-Related Potential 643 E

Event-Related Potential, Fig. 1 (a) Typical stimulus- Negative voltage is plotted upwards by convention. (b) evoked average ERP waveform. The abscissa indicates Typical voltage distribution over the scalp, corresponding time from the onset of the stimulus, and the ordinate with the P3 peak latency indicates the microvolt value for a specific electrode. such as principal component analysis can some- In view of the above considerations, it is not times be useful in identifying latent ERP compo- useful to define a particular ERP component in nents and their contributions to the observed ERP terms of its polarity, latency, and scalp distribu- over the scalp. However, these techniques have tion. Peak latency and scalp distribution may significant limitations (Handy 2005; Luck 2005; differ between trials, conditions, and individuals, Picton et al. 2000). Another potential pitfall con- and even the polarity of a component may vary cerns the variability in timing of some ERP com- depending on the placement of the reference ponents. Not only can there be large variability of electrode. Modern definitions of ERP compo- the average component latency across individuals nents acknowledge that a component may occur or groups but also substantial variability in the at different times under different conditions and timing of single-trial ERP components. Both emphasize that two components are the same if cases may pose significant problems for the they arise from the same neuroanatomical struc- investigator, because an increase in latency vari- ture(s) and represent the same cognitive function ability results in a decrease in peak amplitude of (Luck 2005). the average (across individuals or trials). For example, two experimental conditions that differ The Physiological Basis of ERP Components in latency variability may appear to differ in Little is known about the physiological basis of component amplitude when examined in an aver- ERP components. It is widely accepted that ERP age ERP, even when this is not the case in the components reflect the intracortical currents single-trial waveforms. Investigators should take induced by excitatory and inhibitory postsynaptic this possibility into account when examining and potentials, which are triggered by the release of measuring ERP components (Picton et al. 2000). neurotransmitters. If many individual neighbor- Indeed, sometimes it pays off to attempt to mea- ing neurons with a similar orientation receive sure single-trial estimates of an ERP component a similar excitatory or inhibitory input at approx- and use the trial-to-trial variability in component imately the same time, then the summation of the latency or amplitude to address scientific resulting postsynaptic potentials results in questions. a measurable voltage at the scalp (Luck 2005). E 644 Event-Related Potential

Thus, ERP components reflect the postsynaptic component of the ERP. Then, if it has been effects of neurotransmitters such as glutamate established that ERP component X reflects cog- and GABA and indirect modulatory effects nitive process Y, one can investigate whether an from neuromodulators such as norepinephrine, experimental manipulation or mental state/trait dopamine, and serotonin. Biophysical consider- (e.g., psychopathology) affects process Y by ations suggest that the contribution of subcortical measuring its effect on component X. In particu- structures to the scalp-recorded EEG is small, and lar, an effect on the component amplitude sug- hence, most ERP components reflect primarily gests a change in process Y or a change in the cortical activity. Whether an ERP component input to this process. For example, patients with has a positive or negative polarity depends on obsessive-compulsive disorder exhibit an many neurophysiological and nonphysiological increased amplitude of the error-related negativ- factors and is little informative about the neural ity, an ERP marker of internal error detection. origin or functional significance of the compo- This finding confirms previous notions of nent (Handy 2005). a dysfunctional action-monitoring circuit in With regard to the origin of ERP components, obsessive-compulsive disorder. Furthermore, an an important distinction can be made between effect on the peak latency of component traditional and synchronized oscillation theories X suggests that the manipulation or mental of ERP generation (Klimesch et al. 2007). state/trait has changed the duration of processes According to the traditional view, ERP compo- preceding and including process Y. In contrast, nents reflect phasic bursts of activity in one or an effect on reaction speed in the absence of an more brain regions that are triggered by experi- effect on the peak latency of component mental events of interest. As explained above, X suggests a change in the duration of processes this view treats the ongoing EEG as background following process Y. For example, it is well noise that obscures the ERP signal of interest and known that the presentation of a warning signal deals with that noise through data-averaging pro- can speed up the reaction to an imperative stim- cedures. The synchronized oscillation hypothesis ulus. ERP researchers have increased our under- challenges this approach and instead proposes standing of this phenomenon by showing that the that ERP components are generated when an benefit in reaction speed is largely restricted to event leads to the resetting of the phase of ongo- the time interval between an early ERP marker of ing oscillations in the EEG, such that peaks and spatial attention shifts and an ERP marker of troughs in the oscillatory waveform become hand-specific motor preparation, the lateralized aligned to the resetting event. When aligned in readiness potential. this way, oscillatory peaks and troughs in the Of course, the logic outlined above depends on ongoing EEG are evident in the ERP waveform, the validity of any given ERP component as even in the absence of transient bursts of neural a marker of a specific mental process. In the activity. Empirically distinguishing between past decades, a large amount of research has these two theories has proven difficult for focused on validating ERP components, and a variety of methodological reasons. although there are many ongoing debates in the scientific literature, significant progress has been ERP Components as Markers of Mental made in refining hypotheses about the functional Processes significance and neural origin of ERP compo- The study of ERPs has been of great importance nents (Key et al. 2005; Rugg and Coles 1995). for our understanding of mental processes, by This is particularly true for early ERP compo- augmenting traditional, behavioral measures nents such as the P1 and N1 (Fig. 1a). It is gen- such as reaction speed and accuracy (Rugg and erally held that these components reflect aspects Coles 1995). This approach is based on the of stimulus encoding in modality-specific percep- assumption that changes in a certain cognitive tual areas, such as visual or auditory cortex. Vol- process are selectively expressed in a particular untary or involuntary changes in the amount of Event-Related Potential 645 E attention paid to a particular stimulus lead to specific neurocognitive processes (Carozzo amplitude modulations of the P1 and N1 compo- et al. 2006;Pogarelletal.2006). To that end, nents. Another prominent example of a “sensory” researchers examine whether and how the drug ERP component with a source in modality- changes the corresponding ERP components. specific perceptual areas is the mismatch nega- This often allows for more detailed conclusions tivity. This is a negative deflection with a typical than examining behavioral measures alone. For latency of 100–250 ms that occurs in response to example, ethanol, which has sedative effects, an odd stimulus in a sequence of stimuli, regard- has been found to decrease P3 amplitude, less of whether the subject is paying attention to whereas caffeine increases P3 amplitude, the sequence. suggesting that these drugs affect high-level E Some other prominent ERP components are stimulus-encoding processes. Another example not sensory in nature but reflect central cognitive concerns the P50 wave, an ERP component that processes. Important examples are the N2 and P3 is used for the assessment of sensory gating – the components (Fig. 1a), both of which are sensitive habituation of responses to repeated stimuli. In to contextual variables, such as the relationship healthy subjects, there is an inhibition of respon- between the eliciting stimulus and the subject’s siveness, that is, a diminished P50 to repetitive goal of the task and the subjective probability and stimuli – an adaptive mechanism to prevent novelty of the stimulus. The scalp distribution overstimulation. The NMDA receptor antago- and latency of these components are highly var- nist ketamine and the antipsychotic haloperidol iable across different task contexts. The N2 has disrupt P50 suppression, indicating that these been associated with various mental processes, drugs modulate sensory gating. Another ERP including response inhibition and conflict detec- measure, the loudness dependence of the audi- tion. The P3 is thought to reflect updating of tory evoked potential (LDAEP), has been pro- contextual memory representations or temporal posed as a valid indicator of central serotonergic filtering of motivationally significant stimuli and function in humans. This measure is assessed its latency is thought to index the end of stimulus using the N1/P2 component of the auditory evaluation processes. Another cognitive ERP evoked potential and reflects the reactivity of component is the error-related negativity, the auditory cortex. Thus, this ERP measure is a negative deflection immediately following erro- used as a marker of neuromodulatory function, neous responses that is clearly visible in the rather than a cognitive function. response-locked ERP. There is much evidence that the error-related negativity reflects the Investigating ERPs Using Drug Actions response of the dopamine system to unfavorable Since ERPs reflect functional aspects of outcomes and events. Finally, there are a number neurotransmitters and neuromodulators, drugs of ERP components that are directly related to affecting particular neurotransmitter or motor processes. The most important example is neuromodulator systems are used to investigate the Bereitschaftspotential or readiness potential, theroleofthesesystems in the generation of a measure of activity in the motor cortex that is ERP components (Carozzo et al. 2006;Pogarell leading to voluntary muscle movement. et al. 2006). A limitation of this approach is that A derived measure, the lateralized readiness most available drugs are not selective for potential, reflects the relative activation of the a single system, which complicates the interpre- left and right motor cortex and this has been tation of the results. One exception is a class of very important for the study of covert aspects of drugs, selective serotonin reuptake inhibitors motor preparation (Rugg and Coles 1995). (SSRIs), which selectively increases the amount of serotonin in the brain. Accordingly, SSRIs Investigating Drug Actions Using ERPs have often been used to investigate the role of One use of ERP methodology in psychopharma- serotonin in the generation of different ERP cology is to investigate the effects of a drug on components. Using this approach, it has been E 646 Event-Related Potential shown that serotonin affects the LDAEP reflecting the neurological pathology causing strongly, but is not involved, for example, in schizophrenia, because the P3 amplitude reduc- the generation of the P3, which is modulated by tion is not affected by neuroleptic medication and cholinergic, dopaminergic, and noradrenergic can also be found in remitted schizophrenics, drugs. The mismatch negativity is blocked by relatives of schizophrenic patients, and other sub- NMDA receptor antagonists, indicating that the jects at risk of developing schizophrenia. Thus, mismatch negativity critically depends on the P3 amplitude may be a sensitive marker but is glutamatergic neurotransmission. These and not a specific marker for schizophrenia and is many other findings have led to an increased therefore not used in the diagnostic work-up. understanding of the neural basis of ERP com- However, there are indications that in schizo- ponents. This, in turn, has informed theories phrenic patients, the P3 may predict treatment of their functional significance. For example, response. the finding that the error-related negativity is modulated by dopaminergic drugs has Advantages and Limitations of Event-Related strengthened existing views that link this ERP Potentials component to the literature on dopaminergic The major advantage of ERPs is their fine tem- reward-prediction errors. poral resolution (on the order of milliseconds), indicating that ERPs reflect what is happening in The Role of ERPs in Psychiatry: Sensitivity and the brain at the very same moment. Another Specificity advantage of ERPs is that electroencephalogra- ERPs are not only important research instruments phy is noninvasive and cheap compared with but are also useful as clinical instruments in neu- other brain imaging methods. An additional con- ropsychiatry (Pogarell et al. 2007). ERPs can be venience is that there are clear and widely agreed- used in the diagnostic work-up of a wide range of upon guidelines for how ERP studies should be neuropsychiatric disorders as well as in monitor- conducted, analyzed, and reported (Picton ing the course of the disorders and the prediction et al. 2000). The primary limitation of ERPs is of treatment responses. To be useful in the diag- that it is not possible to determine the neuroana- nostic work-up, an ERP component has to be tomical generator of an ERP component from the sensitive enough to detect the disorder but also measured scalp potentials alone. Furthermore, sufficiently specific for the disorder to rule out the geometrical orientation of neurons must be alternative explanations. more or less parallel in order to detect the neural Alzheimer’s disease is consistently related to activity at the scalp. Signals from structures smaller P3 amplitudes and prolonged P3 laten- located deep within the brain are particularly cies. Using the P3 component, Alzheimer’s hard to measure. Finally, during the averaging patients can be diagnosed with high sensitivity procedure for isolating the ERP from the EEG, and specificity (up to 88.5 %). Furthermore, the all activity that is not time-locked to the event of P3 is effective in both monitoring and predicting interest is lost. In order to examine that informa- the treatment response of Alzheimer’s patients to tion, other electrophysiological methods are cholinesterase inhibitors. Thus, the P3 may be an needed. important instrument not only in the diagnostic work-up but also in the monitoring and prediction of the treatment response in Alzheimer’s disease. This tool is still underutilized in the clinic, pre- Cross-References sumably because the P3 has not been generally accepted as a valid biomarker for Alzheimer’s ▶ Attention disease. Schizophrenic patients also show ▶ Caffeine a decreased P3 amplitude. However, this is gen- ▶ Electroencephalography erally considered a trait marker rather than ▶ Psychophysiological Methods Ex Vivo 647 E

References Cross-References

Carozzo S, Fornaro S, Garbarino S, Saturno M, Sannita ▶ Electroencephalogram WG (2006) From neuroscience to application in neu- ▶ Event-Related Potential ropharmacology: a generation of progress in electrophysiology. Clin EEG Neurosci 37:121–134 Handy TC (ed) (2005) Event-related potentials: a methods handbook. MIT Press, Cambridge, MA Key A, Dove G, Maguire MJ (2005) Linking brainwaves Evidence-Based Guidelines to the brain: an ERP component primer. Dev Neuropsychol 27:183–216 Klimesch W, Sauseng P, Hanslmayr S, Gruber W, Definition Freunberger R (2007) Event-related phase reorganiza- E tion may explain evoked neural dynamics. Neurosci A series of statements, based on systematic Biobehav Rev 31:1003–1016 Luck SJ (2005) An introduction to the event-related poten- searching of relevant scientiﬁc literature and crit- tial technique. MIT Press, Cambridge, MA ical appraisal of relevant sources, usually reached Picton TW, Bentin S, Berg P, Donchin E, Hillyard SA, through consensus and designed to guide clinical Johnson R Jr, Miller GA, Ritter W, Ruchkin DS, Rugg practice. Greatest weight is given to evidence at MD, Taylor MJ (2000) Guidelines for using human event-related potentials to study cognition: recording the top of the “hierarchy” (meta-analyses and standards and publication criteria. Psychophysiology ▶ randomized controlled trials) with stronger rec- 37:127–152 ommendations than are possible when evidence is Pogarell O, Mulert C, Hegerl U (2006) Event related derived solely from less well-designed studies. potentials and fMRI in neuropsychopharmacology. Clin EEG Neurosci 37:99–107 Pogarell O, Mulert C, Hegerl U (2007) Event- related potentials in psychiatry. Clin EEG Neurosci 38:25–34 Evidence-Based Medicine Rugg MD, Coles MG (eds) (1995) Electrophysiology of mind: event-related potentials and cognition, Oxford psychology series. Oxford University Press, Synonyms Oxford EBM

Event-Related Potential Definition Components ▶ Evidence-based medicine aims to apply evi- Synonyms dence gained from the scientiﬁc method to certain parts of medical practice. It seeks to assess the ERP components quality of evidence relevant to the risks and ben- eﬁts of treatments (including lack of treatment).

Definition

Systematic response of the electroencephalo- Ex Vivo gram to a particular sensory, cognitive, or motor event that is generated in a given neuro- Definition anatomical structure when a specific mental operation is performed. The naming of these The term originates from Latin and means “out of components often reflects their polarity (P for the living”; it refers to an experiment that is done positive, N for negative voltage) and their order in or on living tissue and at least partially outside of occurrence. the organism. For example, for the measurement E 648 Excessive Sleepiness of ex vivo receptor binding, an animal can be Definition treated with a test compound in vivo, followed by removal of the brain, exposure of brain slices There are more than 100 known excitatory amino with a radioligand specific for that binding site acids (EAAs), and the large majority of them are in vitro, and subsequent quantification of the nonprotein-forming amino acids initially purified amount of radioactivity in brain areas of interest. from algae or fungi (Lubec and Rosenthal 1990). The degree to which radioactivity is reduced due The endogenous EAAs glutamate (Glu) and to competitive binding of the test substance can aspartate act in the nervous system as excitatory be taken as a measure of receptor occupancy. neurotransmitters; they are released from neurons and they induce neuronal excitation via ionotropic and metabotropic Glu receptors (iGluRs and mGluRs). Related endogenous Excessive Sleepiness molecules like N-acetylaspartylglutamate (NAAG) could also belong to the group of Synonyms EAAs, but they have no demonstrated neurotransmitter properties. EAAs are usually grouped Excessive daytime sleepiness; Narcolepsy to distinguish them from amino acids such as GABA, glycine, or taurine exerting inhibitory effects on neuronal cells. Excitatory neurotrans- Definition mission is present in central and peripheral nervous system, and in the periphery, EAAs A subjective report of difficulty in maintaining the contribute to the regulation of gastrointestinal alert-awake state, usually accompanied by a rapid motility, pain sensation, as well as respiratory entrance into sleep when the person is sedentary. and cardiovascular functions. In nonneuronal cells, Glu receptors and transporters exert a role in the control of proliferation, immune response, Cross-References and bone tissue dynamic (Gill and Pulido 2005).

▶ Hypersomnolence: Central Disorders Pharmacological Properties

Excitatory Amino Acids and Their History Antagonists Glu is the most abundant excitatory neurotransmitter in the brain. The first indications that Glu Linda Lundstro¨m1, Will Spooren1, Silvia Gatti exerted excitatory actions on cerebral cortex McArthur1 and F. Hoffmann La Roche2 were obtained by Hayashi in 1954, and later, 1Pharmaceuticals Division, Hoffmann-La Roche observations by Watkin and colleagues showed Ltd, CNS Discovery Functional Neuroscience, that Glu can depolarize and excite individual Basel, Switzerland neurons in the cat spinal cord. However, it took 2Pharmaceutical Research and Early the scientific community a long time to realize Development Department, Roche Innovation that Glu was functioning as a neurotransmitter, Center, Basel, Switzerland mainly due to its very high abundance in the brain and its involvement in important metabolic pathways. Full acceptance of the neurotransmitter Synonyms role of Glu was achieved only with the characterization of selective agonists and antagonists for Excitatory amino acid transmitters; Excitatory all Glu receptors (Roberts et al. 1981). The last neurotransmitters decade has seen several attempts to exploit the Excitatory Amino Acids and Their Antagonists 649 E therapeutic potential of Glu receptor ligands fast excitatory transmission in the brain. The since molecular psychiatry and behavioral psy- native AMPAR contains different combinations chopharmacology have been instrumental in of the four subunits: GluR1–4. In the predomi- highlighting the possibilities of a pharmaco- nantly expressed GluR2 subunit, an RNA-editing logical modulation of Glu in diseases like schizo- site is present in the center of the TM2 loop. Such phrenia and treatment-resistant depression editing results in an amino acid substitution (TRD). (a neutral glutamine is changed to a positively charged arginine residue) which reduces the per- EAA Receptors and Selective Agonists meability of Ca2+ ions through the channel. The Glu is a flexible chiral molecule that can adopt functional diversity of AMPAR subunits is fur- E nine staggered conformations in physiological ther enhanced by additional RNA editing as well conditions by rotations around two of its carbon as alternative splicing. Together this causes bonds. Because of the large flexibility of Glu, the a large variation in the extracellular region of characterization of the different subgroups of GluR subunits, e.g., the presence of a splice EAA receptors was only possible after the dis- region referred to as flip/flop, and results in recep- covery of conformationally restricted Glu and tor isomers exhibiting different kinetic and phar- aspartate analogues. The observed selective bind- macological properties (Squire et al. 2008). The ing properties of Glu analogues imply that Glu trafficking of AMPAR to and from synapses is interacts with each receptor subtype in a distinct controlled by a complex sequence of interactions conformation (Bunch and Krogsgaard-Larsen with several proteins. Moreover, the AMPAR M1 1992). Agents exerting a specific modulatory domain is tightly interacting with regulatory pro- role on the effects of EAAs are also of therapeutic teins (TARPS), which specifically control the relevance in CNS disorders and are listed accord- incorporation of the receptor into the synapses ingly in Table 1. in association with long-term potentiation (LTP) or long-term depression (LTD) events affecting EAA and iGluRs the synaptic plasticity. iGluRs are ion channels which share a common The first generation of selective AMPAR ago- genetic ancestor and are divided into subclasses nists (and antagonists) was based on the AMPA depending on their ability to interact with three structure (isoxazole derivatives), and they were different Glu analogues: NMDA (N-methyl- used to demonstrate the most relevant features of D-aspartic acid), AMPA (a-amino-3-hydroxy-5- AMPAR: (1) rapid deactivation (channel closure methyl-4-isoxazolepropionic acid), and kainic upon Glu removal), (2) desensitization (channel acid (KA, 2-carboxy-3-carboxymethyl-4- closure during continuous exposure to Glu) due isopropenyl-pyrrolidine). Each iGluR consists to a conformational change of the extracellular of four protein subunits, and each subunit in domain, (3) less pH sensitivity than NMDA turn contains a large extracellular domain with- receptor, and (4) the presence of phosphorylation holding the orthosteric binding site (the binding sites for kinases (PKC, PKA, and CAMKII). site for the endogenous ligand), four transmem- More recently, AMPA potentiators or ampakines brane (TM) domains, and an intracellular have been identified which modulate the C-terminal domain responsible for anchoring AMPAR by interacting at allosteric sites. and trafficking. The TM2 in each subunit forms Ampakines (e.g., CX717) have been shown to a loop inside the cell membrane to create the stabilize the receptor in the channel-open state lining of the pore of the ion channel. The ion prolonging ion flux and reducing desensitization. permeability properties of iGluRs are therefore Generally, ampakines exhibit cognitive- determined by the amino acid residues contained enhancing properties while compounds (e.g., in TM2 (Squire et al. 2008). CX614, CX929, and CX1837) specifically AMPA receptors: (AMPAR) are Na+/K+ ion interacting at the cyclothiazide-binding site of channels, known as the principal transducers of the AMPAR also induce the expression of E 650 Excitatory Amino Acids and Their Antagonists

Excitatory Amino Acids and Their Antagonists, Table 1 Ligands for the different excitatory amino acid (EAA) receptors described in the chapter Allosteric Noncompetitive Receptor Agonist modulator Competitive antagonist antagonist AMPAR AMPA CX717 DNQX GYKI-53784 Kainate CX614 CNQX CP-456,022 L-Quisqualate CX929 Tezampanel Perampanel CX1837 NGX426 Topiramate KAR Kainate DNQX AUBAs Domoate CNQX NS3763 Acromelic acid Tezampanel Joro spider toxin (JSTX) L-Quisqualate LY382884 Arachidonic acid AMPA LY466195 Topiramate ATPA UBP203 Willardiine UBP316 (ACET) NMDAR NMDA D-a-aminoadipate MK-801 (dizocilpine) Glycine D-2-amino PCP (phencyclidine) phosphonovalerate D-cycloserine Spermine AP-5 Memantine Homoquinolinic Spermidine AP-7 Dextromethorphan acid Neurosteroids LY274614 Dextrorphan Argiotoxin Ketamine Ifenprodil (NR2B) Felbamate (NR2B) RO256981 (NR2B) CP-101,606 (NR2B) EVT101 (NR2B) Kynurenic acid Riluzole Competitive Positive allosteric Negative allosteric Agonist antagonist modulators (PAM) modulators (NAM) mGluRs 1S,3R-ACPD Group I L-Quisqualate MCPG (S)-3,5-DHPG LY367366 mGlu1 LY367385 RO674853 CPCCCEt YM298198 BAY36-7620 EM-TBPC A-841720 JNJ16259685 mGlu5 (S)-3,5-DHPG DFB SIB-1757 CPPHA SIB1893 CDPPB MPEP ADX47273 MTEP VU-29 Fenobam (NPL-2009) ADX63365 ADX10059 AFQ-056 ADX48621 STX107 (continued) Excitatory Amino Acids and Their Antagonists 651 E

Excitatory Amino Acids and Their Antagonists, Table 1 (continued) Competitive Positive allosteric Negative allosteric Agonist antagonist modulators (PAM) modulators (NAM) Group II LY354740 L-CCG-I MNI135 LY404039 LY341495 RO676221 LY2140023 MCPG RO718216 HYDIA MGS0039 mGlu2 LY487379 BINA PTBE E AZ1007992 MRLSD-650 ADX71149 Group III (S)-AP4 MAP4 L-AP4 DCG-IV (S)-SOP LY341495 (1S,2R)APCPr mGlu4 PHCCC SIB1893 MPEP VU3423 VU155041 mGlu7 AMN082 MDIP (allosteric) MMPIP mGlu8 (s)-3,4-DCPG Thiomethylanilide A/B

neurotrophins (such as BDNF) and exhibit anti- and pharmacological properties. NMDAR- depressant properties. containing subunit NRA2B exhibits, for instance, The NMDA receptor (NMDAR) consists of the highest affinity for glycine and is inhibited a heterotetramer assembled from different sub- only by micromolar concentrations of Zn2+. Dur- units: NMDAR1 (1a,b to 4a,b) contains the ing membrane-resting potential conditions, Mg2+ glycine-binding site; NMDAR2 (A–D) contains ions are binding to and blocking the NMDAR Glu-, polyamine-, Zn2+-, and proton-binding sites; channels, and membrane depolarization (usually and NMDAR3 (A and B) has a modulatory role by activation of AMPAR) is required to release (Gereau and Swanson 2008). Subunit R1 is the Mg2+ blockade. Activation of the NMDAR required for channel formation, while R2A–R2D allows Ca2+ influx to initiate numerous intracel- play an important role in determining the affinity lular processes responsible for synaptic plasticity. for both Glu and coagonists glycine or D-serine and Hyperactivation of the NMDAR, on the other modulating the receptor activity. The restricted hand, causes excitotoxicity and this is why the NMDA analogue homoquinolinic acid which dis- activation process is strictly controlled by bind- plays some selectivity against the NR2B- ing of several endogenous ligands and interaction containing receptors can also be included among partners. Binding of polyamines (spermine and receptor agonists. spermidine) and neurosteroids (e.g., dehydroepi- In neurons, NMDARs are mostly hetero olig- androsterone) to allosteric sites on the NMDAR omers of 2xR1 and 2xR2 subunits forming positively modulates current amplitude; and for functional channels with different physiological this reason, some polyamines can be excitotoxins E 652 Excitatory Amino Acids and Their Antagonists

(Bunch and Krogsgaard-Larsen 1992). In spite of domoate selectively activate KARs at low con- the high concentrations of glycine present in centrations. Quisqualic acid activates several Glu extracellular fluids, the glycine site of the receptors: KARs, AMPARs, and mGluRs. NMDAR is possibly not always saturated AMPA is acting as a partial agonist at recombi- because of the presence of efficient glycine trans- nant GluK1 receptors, with no effect on GluK2; porters (GlyT1 and GlyT2). Clinical evidence of and the AMPA analogue ATPA shows selectivity NMDA hypofunction in schizophrenia has trig- toward GluK1 over AMPAR. Also, willardiine gered attention for the pharmacological modula- analogues show selectivity for GluK1 over tion of GlyT1, and inhibitors are currently under AMPA subunits. development as antipsychotics. The kainic acid receptors (KAR) form EEA and mGluRs heteromeric cationic ion channels assembled mGluRs are G-protein-coupled receptors from five different subunits, GluK1–5 (GPCRs) and they are responsible for slow excit- (according to the new IUPHAR nomenclature, atory/inhibitory transmission. Distinct from the GluR5–7 are now named GluK1–3 and KA1 majority of GPCRs, mGluRs exist as functional and KA2 are named GluK4 and 5). Glu activity homodimers where a cysteine-rich domain con- at different KAR subunits is exerted in the low nects the two monomers of the receptor. mGluRs mM range and they are involved in NMDA- are characterized by a large extracellular domain independent LTP. Similar to the AMPAR, RNA and seven TM domains. The extracellular domain editing occurs in KAR (e.g., at the Q/R site in of each mGluR monomer contains the TM2 on subunits GluK1 and GluK2), and the Glu-binding site located in a so-called bilobed C-terminal domains of GluK1–3 are edited by structure (usually referred to as the Venus flytrap alternative splicing (Gereau and Swanson 2008). domain). The Venus flytrap can have an open or The fully edited (modified by both RNA editing closed configuration in the absence or presence of and splice variation) variant of GluK2 is the most an agonist, respectively. The molecular mecha- abundantly expressed subunit in the adult CNS. nism of activation of mGluRs is not completely The high expression of the KARs is seen in the understood, but agonist binding is known to sta- synaptic connection between the hippocampal bilize the closed form of the Venus flytrap mossy fibers and CA3 pyramidal cells. Neuro- domain and result in specific conformational transmitter release modulated by KARs facili- changes in the extracellular and TM domains tates presynaptic forms of short- and long-term which recruits and activates specific G proteins. synaptic plasticity. When expressed at postsyn- Eight subtypes have been identified in the family aptic locations, KARs also induce synaptic cur- of mGluRs (mGlu1–8), classified into three major rents of small amplitude with slow kinetics. The groups (I–III) based on their sequence homology, cellular subunit localization of KAR is dynamic, second messenger coupling, and pharmacology. and AMPAR stimulation is known to increase Splice variants of mGluRs are mainly found in GluK2 postsynaptic localization, while both the intracellular carboxy terminals affecting the GluK2 and GluK5 expressions are decreased at G-protein coupling efficiency and have to date the presynapse. The understanding of the func- been identified for mGlu1, mGlu3, and mGlu5 tion of KARs is lacking behind mainly because of (Gereau and Swanson 2008). Glu exhibits differ- the relative shortage of selective pharmacologi- ent affinity for the different mGluRs, spanning cal tools. Selective agonists for the KARs are all from the mM to the mM range. natural products isolated from seaweed or fungi. EAAs interacting with the mGluR orthosteric

Domoate and acromelic acid are both more site exhibit fast Kon/Koff rate and a limited capac- potent agonists than the prototypic agonist KA ity of discrimination between the three sub- (Bunch and Krogsgaard-Larsen 1992). KA and groups. Among them, L-AP4 helped the related compounds exhibit also nondesensitizing pharmacological definition of mGluRs long agonist activity at the AMPA receptor, while before the cloning of the receptors and is Excitatory Amino Acids and Their Antagonists 653 E probably the most characterized mGluR agonist. Coexpression of NMDA and mGlu5 receptors The restricted Glu analogue 1S,3R-ACPD in vitro and in vivo has revealed the presence of (highest affinity for groups I and II) was the first a tonic mGlu5-mediated potentiation of NMDAR identified mGluR ligand that did not interact with activity. This observation is the reason for the iGluRs (Gereau and Swanson 2008). Allosteric current search for mGlu5 PAM with predicted binding sites, which are located in the TM region, antipsychotic properties. The benzaldazine DFB have allowed the characterization of functionally molecule was earlier identified as a PAM on more selective ligands. mGluR enhancers can mGlu5; and among its derivatives, there are increase potency and/or efficacy of an agonist both NAM and neutral ligands, all showing partly and are generally identified as positive allosteric overlapping binding sites in the TM domain. E modulators (PAM). Noncompetitive antagonists Compounds like CPPHA, CDPPB, ADX47273, can be referred to as negative allosteric modula- and VU-29 enhance mGlu5 activity, facilitate tors (NAM) and are reducing the effects of an hippocampal synaptic plasticity, and have there- agonist. Ligands which bind to the allosteric site fore a potential use as antipsychotics and cogni- without apparent changes in receptor pharmacol- tive enhancers. The ADX63365 mGlu5 PAM is ogy are named silent allosteric modulators presently in development for the treatment of (SAM) (Lutz and Kenakin 1999). The search for schizophrenia. allosteric ligands of mGluRs has allowed the Groups II (mGlu2 and mGlu3) and III discovery of compounds that are able to discrim- (mGlu4, mGlu6, mGlu7, and mGlu8) mGluRs inate between very similar mGluRs, e.g., within are predominantly expressed at the presynaptic group II and group III mGluRs. A similar effort terminal or in glial cells (mGlu3). They inhibit has recently resulted in the discovery also result adenylate cyclase, activate GIRK channels, and in the discovery of new classes of compounds inhibit presynaptic Ca2+ with an overall inhibi- with multiple PAM/NAM activities on different tory effect on neurotransmitter release. The first mGluRs. high-affinity in vivo active agonist selective for Group I mGluRs (mGlu1 and mGlu5) are pre- group II was the Glu analogue LY354740 dominantly expressed postsynaptically where (bicyclic structure). Several modifications have they are positioned by scaffold proteins (acts as been made on this scaffold, changing both its regulators of signaling pathways by binding to receptor affinity and functional properties. An and localizing its components to specific areas) in agonist derivative from this class LY404039 close contact with the postsynaptic density. The (with the prodrug LY2140023) was recently activation of these receptors stimulates shown to have antipsychotic and anxiolytic phospholipase C, potentiates L-type Ca2+ chan- effects in phase II clinical trials. Several mGlu2 nels, and stimulates GIRK channels (G-protein- PAMs have been characterized in preclinical activated inwardly rectifying K) in recombinant models to demonstrate antipsychotic profile. systems. L-Quisqualate, also activating AMPAR, Compounds like LY487379, BINA, PTBE, is the most potent group I agonist, while (S)-3,5- AZ1007992, MRLSD-650, and ADX71149 are DHPG is a moderately selective agonist at the the results of this search, while selective mGlu3 mGlu5, and to date, no selective agonist has PAMs in vivo characterization. been identified for mGlu1. The very first PAMs For the group III receptors, (S)-AP4, identified for mGluRs were a class of compounds (S)-SOP, and (1S,2R)APCPr are the most potent (e.g., RO674853) potentiating the agonist- agonists, and the (S)-3,4-DCPG ligand shows induced response at mGlu1. Enhancing the some selectivity for mGlu8. Because of the lack mGlu1 receptor activity has been shown, both of selective ligands, the pharmacology of the from animal model and genetic studies, to be group III receptors is still the least developed of beneficial in cerebellar ataxia. the mGluRs. The first mGlu4 PAMs, such as A complex interaction can be demonstrated PHCCC, SIB1893, and MPEP, were originally between mGlu5 and NMDA receptors. identified as NAMs at group I mGluRs. E 654 Excitatory Amino Acids and Their Antagonists

More potent and selective mGlu4 PAMs are the open-channel blocker for the NMDAR, is com- VU3423 and VU155041 compounds which, in monly used as dissociative anesthetic and at low preclinical models, have shown to have doses against neuropathic pain. In treatment- a function in neurodegenerative disorders, partic- resistant depression (TRD), the acute administra- ularly on reversal of motor deficits in Parkinson’s tion of ketamine is able to improve mood and disease. For the mGlu7 receptor, there are few anxiety while reducing suicidal thoughts in mat- reported PAMs to date, and AMN082 was ter of hours and with a long-lasting effect. The recently identified as an mGlu7-selective alloste- possibility to discriminate, in a pharmacological ric agonist. Initial studies with this compound manner, between the antidepressant properties show activation of mGlu7 to be linked to and dissociative/euphoric effects mediated by anxiolytic-like effects in rodents. Two PAMs NMDA antagonists is currently investigated for mGlu8, Thiomethylanilide A and B, were using selective and high-affinity NMDA2B recently introduced, but in vivo data are still antagonist and Glycine site NMDA receptor awaited. ligands eg. GLYX13 partial agonist (Kew et al. 1998). NMDA2b antagonists (also called EAA Receptor Antagonists polyamine site antagonists) cause a relative selective blockade of the NR2B-receptor subunit iGluR Antagonists (100-fold over NR2A and NR2C). RO256981 NMDAR Antagonists: D-a-aminoadipate and D-2- and CP-101,606 are among the best-known amino phosphonovalerate were among the first antagonists of this kind and the orally active like competitive antagonists selective for the EVT101 could still find some therapeutic appli- NMDAR described in the literature. More potent cation eg TRD. orally active compounds with anticonvulsant and Kynurenic acid, derived from tryptophan neuroprotective properties (like AP-5, AP-7, and catabolism, is an endogenous antagonist at the LY274614) were prepared in the 1990s. These NMDAR with selectivity for the glycine site at competitive antagonists however produced psy- low concentrations while blocking also AMPAR chotic reactions and were soon dismissed in favor and KAR at higher concentrations. A more potent of noncompetitive ligands. The discovery of two partial agonist Glyx13 is a¨lso currently under use-dependent, high-affinity, noncompetitive development for TRD. Riluzole is also antagonists (MK-801 (dizocilpine) and PCP) a glutamatergic modulator with anticonvulsant, binding in the ionic pore only in the open channel neuroprotective, and plasticity-enhancing prop- (commonly referred to as the PCP-binding site) erties which is presently approved for treatment created a lot of interest. However, also these of ALS and a promising candidate for treatment channel blockers had to be dismissed because of of mood disorders. It has several effects on the the euphoric and dissociative central effects brain glutamatergic system: inhibiting Glu responsible for their abuse potential and the release via Na+ channels, increasing Glu trans- induction of memory loss. Few NMDA antago- porter (EAAT1) activity and expression, and nists have found applications in clinical increasing the surface expression of AMPA sub- practice. The open-channel blocker memantine units GluR1 and GluR2. No direct interaction (interacting at the Mg2+-binding site) is well tol- with NMDA or KARs is established although erated in chronic treatment and has shown mild inhibition of NMDAR to prevent Ca2+ entry is but positive effects on cognition and agitation a possible mechanism of action. in clinical trials in Alzheimer disease AMPA and KAR Antagonists: Much progress dementia. Dextromethorphan (and its metabolite has been made in developing selective AMPAR dextrorphan) is a commonly used cough depres- antagonists, while it is only recently that selective sant that inhibits the NMDAR by binding inside KAR antagonists have been disclosed. The cross- the ion channel and might have a potential use for reactivity of AMPA and kainate on GluK1 and children with Rett’s syndrome. Ketamine, also an AMPAR resulted in the initial development of Excitatory Amino Acids and Their Antagonists 655 E antagonists with effect on both receptors. The extracellular binding pocket (the “Venus most commonly used AMPAR antagonists are flytrap”). Potent competitive antagonists for the the quinoxalinediones (such as DNQX and group I receptors (e.g., LY367366) are derived CNQX), which are potent non-NMDA antago- from the (S)-MCPG structure, while LY367385 nists with selectivity for AMPAR (20-fold) over is a selective mGlu1 antagonist. Most potent KARs. Tezampanel is a competitive AMPA/ group II antagonists are derived from L-CCG-I GluK1 antagonist with increased potency, and (e.g., LY341495), while antagonists with better its orally active prodrug NGX426 is the first selectivity could be obtained by derivatization of AMPA/KAR antagonist to be studied in clinical agonist LY354740, e.g., HYDIA and MGS0039. trials for chronic pain, including migraine and Extensive preclinical studies have been E neuropathic pain. Some derivatives of performed with the group II selective antagonists tezampanel are functioning as selective KAR showing antidepressant- and anxiolytic-like GluK1 antagonists (LY382884 and LY466195). effects. The group III mGluRs still lack compet- Selectivity for AMPAR over GluK1 was only itive antagonists with high potency and selectiv- achieved when developing noncompetitive ity, while compounds like MAP4, DCG-IV, and antagonists, e.g., GYKI-53784 and CP-456,022. LY341495 function as antagonists with moderate These AMPAR antagonists do not function as potency. Due to the high similarity of the open-channel blockers but are instead binding in orthosteric binding site of the different mGluRs, the linker regions between the extracellular and the most promising strategy to selectively antag- TM domains, affecting the conformational onize this group of receptors is by targeting the changes induced by the agonist. Another potent allosteric binding site(s) using NAMs. and highly selective, noncompetitive, AMPAR Group I NAM mGlu1: The most commonly antagonist, perampanel, was initially developed used mGlu1 antagonist is the noncompetitive as an add-on therapy to L-dopa in Parkinson’s antagonist CPCCOEt which is structurally disease but is presently under investigation for unrelated to Glu and is binding in the TM domain neuropathic pain and epilepsy. UBP203 and of the receptor. More potent NAMs are UBP316 are potent competitive antagonists with YM-298198, BAY36-7620, and EM-TBPC, enhanced KAR GluK1 selectivity achieved by interacting in the same region of the receptor. SAR studies of the natural product willardiine. Blockade of mGlu1, by antisense oligonucleo- Selective competitive antagonists for the other tides, antibodies, and NAMs, has shown its KAR subtypes are not yet available. involvement in modulation of nociception and Noncompetitive antagonists have so far been chronic pain. A-841720 NAM, structurally dif- identified for the GluK1 and GluK2 subtypes ferent to previous mGlu1 NAMs, has also shown (e.g., the AUBA compounds) and for the GluK1 to be effective in models of nociception and is homomeric KAR (NS3763). These compounds presently under development for pain treatment. are likely to be the starting point of further devel- Antagonists of mGlu1 have been postulated to opment of noncompetitive antagonists. Other have a therapeutic effect in anxiety disorders modulators include the Joro spider toxin which has been confirmed by the potent mGlu1 (JSTX), blocking the unedited GluK2; NAM JNJ16259685. arachidonic acid, primarily blocking homomeric Group I NAM mGlu5: Brain areas expressing GluK2 and GluK1/GluK2 receptors; and mGlu5 receptors (limbic cortex, hippocampus, topiramate, which inhibits excitatory neurotrans- amygdala, and basal ganglia) are known to play mission also through actions on KAR (GluK1) an important role in emotion and motor controls, and AMPARs (Lutz and Kenakin 1999). and mGlu5 was early recognized as a potential target for mood disorders and neurodegenerative mGluR Antagonists diseases involving motor dysfunctions. SIB-1757 Competitive antagonists acting on mGluRs pre- and SIB-1893 were the first selective mGlu5 vent the closure of the two lobes of the NAMs to be identified. They were further E 656 Excitatory Amino Acids and Their Antagonists developed and optimized into the more potent receptors under physiological and pathological and selective MPEP which is the most widely conditions. used mGlu5 antagonist (a prototype for mGlu5 Group III NAM: The recent identification of NAMs). mGlu5 NAMs, such as MPEP and its selective allosteric agonists for mGlu4, mGlu7, more selective derivative MTEP, show a clear and mGlu8 will greatly help to facilitate the phar- anxiolytic- and antidepressant-like profile in macological characterization of these receptors a wide range of preclinical behavioral models. and the discovery of selective NAMs. Very In the search for mGlu5 NAMs, the known anxi- recently a class of pyridine compounds (MDIP olytic compound fenobam was identified, binding and MMPIP) was identified as mGlu7 NAM. to the receptor at the same site as MPEP. After They are likely to help the clarification of the this observation, several pharmaceutical compa- physiological role of mGlu7 in anxiety since con- nies have filed numerous patents on compounds troversial results were seen in mGlu7 knockout acting as mGlu5 NAMs (divided into two major mice and in studies using the allosteric agonist classes: acetylene- and nonacetylene-containing AMN082. compounds). The mGlu5 NAM ADX-10059 recently completed a phase II trial in migraine Conclusions and Perspectives with successful outcome. The same compound The effort placed during the past decades on the was also the first in class to show positive results characterization of the molecular properties of in a phase II trial for gastroesophageal acid reflux EEAs and their antagonists has been rewarded disease. Supported by mGlu5 expression in cor- with the development of some of these ligands tical and basal ganglia structures, mGlu5 NAMs for different therapeutic opportunities. The field have been shown to treat L-dopa-induced dyski- is however still challenging. Further basic nesia in rodent and primate models. MPEP research is required to understand the function has also been shown to protect the nigrostriatal of the glutamatergic synaptic cleft in its entirety, system against toxicity, thus having as well as to clarify the peculiarities and the a neuroprotective function and a possibility to plasticity of the glutamatergic control on GABA prevent disease development. Based on these neurons. Moreover, a number of Glu receptors indications, the AFQ-056 and ADX48621 com- and transporters are still missing selective pounds are in development for reducing L-dopa- ligands, and the definition of molecular determi- induced dyskinesias in Parkinson’s disease. It has nants of receptor cross talk for mGluRs (e.g., been suggested that the loss of FMRP (Fragile mGlu2/5-HT2A) brings further differentiation X mental retardation protein) will result in an between competitive and non competitive enhanced mGlu5 signaling, and the attenuation mGluR ligands. The clinical development of sev- of mGlu5 activity is therefore believed to provide eral EAA receptor ligands (included in Table 1) not only symptomatic relief but also disease mod- was helped by suitable PET ligands (positron ification in fragile X syndrome. NPL-2009 emission tomography, an imaging technique (fenobam), STX107, and AFQ-056 are all in using short-lived radioactive substances to show development as potential therapies for this autis- uptake and distribution of the substances in tis- tic disorder (Jaeschke et al. 2008). sue) that were used during the preparation of the Group II NAM: Preclinical studies in rodents different clinical trials and possibly could be are supportive of a therapeutic potential for could be also of help both in diagnostic terms mGlu2/3 NAM in mood disorders and as cogni- and to identify responders. tive enhancers. A class of benzodiazepines (e.g., Proof of concept clinical studies for the differ- MNI135, RO676221, and RO718216) has been ent pharmacological targets brought forward by disclosed as potent and in vivo active mGlu2/3 the glutamatergic hypothesis are certainly long NAM. The discovery of antagonists with selec- awaited. They will help to understand if efficacy tivity for the two subtypes, mGlu2 and mGlu3, is and tolerability of the pharmacotherapy of both also helping to clarify the specific role of these schizophrenia and depression (McArthur and Excitatory Amino Acids and Their Antagonists 657 E

Borsini 2008) will be substantially improved in ▶ Hippocampus future years. ▶ 5-HT2A Receptor If there is, however, an achievement that ▶ In vivo already stands out because of the long-term ▶ Ketamine impact it will hopefully have on the quality of ▶ Knockout/Knockin life of the patients, this must be the observation of ▶ Levodopa, L-DOPA the effects of mGlu5 antagonists in fragile ▶ Long-Term Potentiation and Memory X syndrome. The concrete hope of a cure has ▶ Memantine increased also the interest for the early diagnosis ▶ Membrane Potential ▶ and for a better understanding of the disease Mood Disorders E progression during the ﬁrst years of life. This is ▶ N-Methyl-D-Aspartate Receptor certainly one of the best examples of a successful ▶ Neurodegeneration molecular approach to the therapy of neurodeve- ▶ Neuroprotective Agent lopmental brain disorders. ▶ Neurotransmitter ▶ Nociception ▶ Partial Agonist Cross-References ▶ Phase II Clinical Trial ▶ Receptor ▶ Allosteric Modulators ▶ Receptors: Binding Assays ▶ Allosteric Site ▶ Schizophrenia ▶ Alternative Splicing ▶ Second-Generation Antipsychotics ▶ Alzheimer’s Disease ▶ Second Messenger ▶ AMPA Receptor ▶ Ampakines ▶ Animal Model References ▶ Antagonist ▶ Antidepressants Bunch L, Krogsgaard-Larsen P Subtype Selective Kainic ▶ Antisense Oligonucleotides Acid receptor agonistsDiscovery and approachesto ▶ Anxiety Rational Design Medicinal Research Reviews 2009; ▶ 29, 3-28. Anxiolytics Gereau RW, Swanson GT, editors. The glutamate recep- ▶ Autism tors. Totowa: Humana Press; 2008. ▶ Benzodiazepines Gill S, Pulido O, editors. Glutamate receptors in peripheral ▶ Binding tissue (excitatory transmission outside the CNS). New ▶ York: Kluwer; 2005. Cognition Jaeschke G, Wettstein JG, Nordquist RE, Spooren ▶ Memory W. mGlu5 receptor antagonists and their therapeutic ▶ Cognitive Impairment potential. Expert Opin Therap Patents. 2008;18(2): ▶ Dementia 123–42. ▶ Kew JNC, Trube G, Kemp JA. State-dependent NMDA Depression receptor antagonism by Ro 8–4304, a novel NR2B selec- ▶ Desensitization tive, noncompetitive, voltage-independent antagonist. Br ▶ Dyskinesia J Pharmacol. 1998;123:463–72. ▶ G-Protein-Coupled Receptors Lubec G, Rosenthal GA (eds) (1990) Amino acids chem- ▶ istry biology and medicine. In: Proceedings of the GABAergic Transmission international congress on amino acid research, Vienna ▶ Glutamate 1989. ESCOM Science, Leiden ▶ Glutamate Receptors Lutz M, Kenakin T, editors. Quantitative molecular phar- ▶ Glycine Transporter 1 macology and informatics in drug discovery. Chiches- ▶ ter: Wiley; 1999. GPCR McArthur R, Borsini F, editors. Animals and translational ▶ GIRK Channels models for CNS drug discovery. Amsterdam: Elsevier; ▶ Group II Metabotropic Glutamate Receptor 2008. E 658 Excitotoxicity

Roberts PJ, Storm-Mathisen J, Johnston GA (eds) (1981) Glutamate. Transmitter in the central nervous Excretion system. In: Proceedings of the ﬁrst congress on Gluta- mate in CNS held in Jerusalem in 1979. Wiley, New York Synonyms Squire LR, Darwin B, Bloom FE, Sascha du Lac AG, Spitzer NC. Fundamental neuroscience. 3rd ed. Clearance; Elimination New York: Academic; 2008.

Definition

Excitotoxicity Excretion is the elimination of the drug from the body. Definition

This term was coined by Olney and colleagues in Cross-References the 1970s to describe neuronal necrosis caused by the exposure of CNS tissue to EAAs. These ▶ Distribution neurotoxic lesions affect predominantly post- ▶ Excretion synaptic regions with swollen dendrites, dilated ▶ Liberation perykarial mitochondria, and endoplasmic retic- ▶ Metabolism ulum, while axons and presynaptic terminals are ▶ Pharmacokinetics spared. In the late stage, nuclear pyknosis and vacuolations are apparent. EAA neurotoxic properties can be used in neurobiology to selectively lesion sensitive neuronal populations Executive Functions (e.g., ibotenic acid). Synonyms

Cognitive control; Higher-order cognitive Excitotoxins processing; Supervisory attentional systems

Synonyms Definition Neurotoxin Executive functions are higher-order cognitive processes dynamically involved in the optimization, Definition monitoring, and coordination of lower-order mental mechanisms during the planning, execution, and Excitotoxins are agonists at either of the evaluation of goal-directed thought and behavior glutamatergic receptor subtype (AMPA, (i.e., executive control). Executive functions NMDA, or kainate) receptors and cause damage include cognitive ﬂexibility, inhibition, perfor- or cell death by permitting high levels of calcium mance monitoring, and the regulation of attention ions to enter the cell. The calcium ions then and working memory, which are essential for opti- activate a variety of enzymes including phospho- mal decision making, problem solving, and perfor- lipases, endonucleases, and proteases that can mance adjustment in a constantly changing damage the internal structures of the cell, for environment. These supervisory and regulatory example, DNA and cytoskeleton, potentially processes are implemented in a top-down fashion, leading to cell death. require effort, and are limited by the availability of Expectancies and Their Influence on Drug Effects 659 E cognitive resources. Efﬁcient executive control Definition depends primarily on the integrity and functionality of the prefrontal cortex and is modulated by the Substance-related expectancies are anticipatory ascending monoaminergic systems of the brain. cognitions that explain drug-seeking behavior by providing information about whether a substance will produce a desired effect Cross-References (contributing to behavioral activation) or an undesirable outcome (resulting in behavioral ▶ Pharmaceutical Cognitive Enhancers: avoidance). Expectancies need not be accurate Neuroscience and Society or explicit to guide behavior. E

Impact of Psychoactive Drugs Exocytosis Expectancies help explain how individuals initi- Definition ate and maintain psychoactive drug use. Prior to their own first use of a substance, individuals A process by which the membrane of an intracel- develop beliefs about the effects of drugs based lular vesicle fuses with the plasma membrane of on information gathered from parents, peers, the cell and by which the content of the vesicle is advertising, and media. As individuals associate expelled in the extracellular space and membrane psychoactive drug use with subjectively positive proteins (e.g., receptors) that are incorporated in outcomes, they are more likely to try the sub- the vesicular membrane become exposed on the stance. If the expected effect is achieved, the plasma membrane. expectancy is reinforced. Expectancies, however, can be reinforced by observing the behavior and communication of others, allowing individuals to maintain expectancies without trying the drug. It Exogenous Factors should be noted that most of the extant literature on substance abuse has focused on alcohol- Definition related expectancies, although studies evaluating expectancies for other psychoactive substances External influences on behavior. have demonstrated similar findings. Expectancies gained attention as an explanation for the placebo effect after it was observed that questionable medications were effective in Expectancies and Their Influence on some individuals. It was hypothesized that creat- Drug Effects ing an expectation that the medication would be successful was the key in separating mental pro- Amee B. Patel1 and Kim Fromme2 cesses from chemical processes, which was 1G.V. (Sonny) Montgomery VA Medical Center, supported by the fact that the absence or Jackson, MS, USA misattribution of this expectation led to the failure 2Department of Psychology, The University of of the placebo effect. This concept of expectation Texas at Austin, Austin, TX, USA was also used to explain the disinhibitory effects of alcohol use (MacAndrew and Edgerton 1969). It was argued that disinhibition was a psychologi- Synonyms cal manifestation of the sociocultural belief that alcohol caused a lack of inhibition, rather than an Expectations actual pharmacological effect. Experimental E 660 Expectancies and Their Influence on Drug Effects

Expectancies and Their Influence on Drug Participants actually receive... Effects, Fig. 1 Balanced placebo design depicting Alcohol No alcohol the four groups and measurable effects of the Expectancy experimental manipulation Both pharmacological effects only and expectancy effects (given placebo)

Pharmacological effects only No effects Participants expect to receive...

No alcohol(given Alcohol anti-placebo)

procedures were subsequently developed to test actually received (i.e., received placebo/told pharmacological versus psychological explana- alcohol, received anti-placebo/told no alcohol). tions for drug effects. Clinical drug trials using The placebo was a nonalcoholic beverage placebos were used successfully to test the efficacy designed to mimic an alcoholic drink, whereas of different psychoactive medications, such as the anti-placebo was an alcoholic beverage dis- imipramine, diazepam, and haloperidol. In con- guised as a nonalcoholic beverage. By comparing trast, Penick and Fisher (1965) conducted a study the behavior of those individuals who believed to test expectancies in which students were admin- they received alcohol and actually did to the istered epinephrine or placebo while being told behavior of those who believed they received that they had received a drug that was either sedat- alcohol but did not, researchers were able to ing or stimulating; they found that there were disaggregate the effects caused by alcohol from moderate expectancy effects such that some stu- the effects of simply expecting alcohol. dents reported feeling sedated on the epinephrine. Early alcohol research with the balanced pla- Despite the promise of this area of study, there cebo design demonstrated that both pharmaco- were methodological limitations that called for logical and expectancy effects affected overall a more rigorous experimental design. behavior but that expectancy effects have greater The balanced placebo design corrected for effects on social behaviors (Hull and Bond 1986). these limitations and allowed researchers to sep- Likewise, studies evaluating the effects of pla- arate true pharmacological effects from the cebo versus marijuana found that previous expe- effects induced by expectancy set or instructions rience with marijuana and the subject’s that one has consumed a substance. Applied to expectancies were predictive of difficulties dif- the effects of alcohol, individuals received either ferentiating placebo from active drug. It was an alcoholic beverage or nonalcoholic beverage hypothesized that frequent users were responding and were given information about whether or not to marijuana-related cues (e.g., smell, taste) their beverage contained alcohol (Marlatt and rather than the true potency of the drug. In study- Rohsenow 1980). As illustrated in Fig. 1, four ing chronic pain management, it was found that distinct groups were created; two groups were placebo effects constituted a significant propor- given correct information about the alcoholic tion of pain reduction attributed to analgesics, but content of their drink (i.e., received alcohol/told placebo was not effective for those who held alcohol; received no alcohol/told no alcohol), negative expectancies about the utility of the whereas the other two groups were told that drug. The application of the balanced placebo they were given the opposite of what they design to nicotine studies yielded results that Expectancies and Their Influence on Drug Effects 661 E suggested that the expectation of nicotine in gum tobacco, and cocaine (Patel and Fromme 2009). increased abstinence among smokers trying to Many assessments evaluate both positive, or acti- quit. Mixed results were found in a study of vating, and negative, or inhibiting, expectancies. cocaine versus placebo effects, with some studies As each person has multiple beliefs about using supporting placebo effects and others finding psychoactive substances, it is important to assess pharmacological effects to outweigh placebo both positive and negative expectancies to deter- (Earleywine 2005). These and other findings led mine how these beliefs act together to predict to the reasoning that placebo effects were based behavior. Studies have suggested that positive on people’s beliefs about the effects of the drug; expectancies are more closely aligned with the therefore, these beliefs could be studied outside initiation and maintenance of substance use, E of experimental designs, leading to the study of whereas negative expectancies are associated outcome expectancies as unique predictors of with past or decreased drug use (Jones et al. 2001). psychoactive drug use. Among studies evaluating expectancy effects Substance-related outcome expectancies, or on alcohol use, explicit expectancies have been beliefs about the expected outcomes of the sub- shown to influence both the frequency and quan- stance, have been differentiated into explicit and tity of alcohol consumption, binge drinking, and implicit types based on whether or not the indi- alcohol-related consequences (Jones et al. 2001). vidual is aware of the expectancy. Explicit expec- The relation between these distinct measures of tancies are higher-order cognitive processes that alcohol use and explicit expectancies suggests can be deliberately recalled, reflected upon, and that expectancies shape decisions about alcohol discussed. Implicit expectancies are automatic consumption at many levels. The literature on processes that do not rely on the individual’s tobacco use and expectancies demonstrates that awareness to motivate behavior. Although evi- stronger expected outcomes are found among dence is limited, the current research on explicit smokers, and more robust expectancies predict and implicit expectancies has shown that each smoking after abstinence. Marijuana- and provides a unique contribution in predicting sub- cocaine-related expectancies are similarly asso- stance use (Goldman et al. 1999; Wiers and Stacy ciated with more frequent use of each respective 2006). This is further supported by the existence drug (Patel and Fromme 2009). of divergent explicit and implicit expectancies. Because the individual is aware of his own Implicit Expectancies explicit expectancies, these expectancies are The influence of implicit expectancies on sub- subjected to cortical processing and cognitive stance use has been shown to be as robust as filters such as social desirability. Researchers that of explicit expectancies (Wiers and Stacy have yet to determine the association between 2006). Alcohol use can be predicted by implicit implicit and explicit expectancies, but current expectancies among college students, at-risk hypotheses are that they are different facets of youth, and community samples. Implicit expec- the same cognitive construct, discrete cognitive tancies are also associated with greater tobacco processes, or temporally related constructs (i.e., use, increased cravings for tobacco, and a higher explicit cognitions precede implicit cognitions likelihood of relapse after smoking cessation. such that learning becomes more automated Preliminary studies evaluating implicit expec- over time, Wiers and Stacy 2006). tancy effects on marijuana, opiates, and cocaine suggest that implicit expectancies are important Explicit Expectancies factors in predicting drug use (Rooke et al. 2008). Explicit expectancies are measured using surveys Implicit expectancies are measured using that ask individuals to report their expectations experimental tasks that attempt to isolate differ- about the behavioral and affective outcomes of ent aspects of implicit cognition. Measurable using a psychoactive drug. Expectancy measures areas of implicit cognition include attentional have been developed for alcohol, marijuana, bias, arousal, and memory associations. E 662 Expectancies and Their Influence on Drug Effects

Attentional bias refers to the identification of expectancies, which are related to decisions to drug-related cues faster than cues not typically reduce drug use (Jones et al. 2001). The atten- associated with drugs. Drug abusers demonstrate tional retraining intervention was designed to greater attentional bias toward drug-related cues. specifically target and reduce attentional bias for Implicit arousal assesses the level of physiologi- drug-related stimuli (Wiers and Stacy 2006). cal arousal and/or the level of arousal-related Interventions that target both types of expec- cognitions in response to the presentation of tancies may be more effective in achieving drug-related cues. Increased cognitive or physio- sustained changes in substance use. This is logical arousal in response to substance-related supported by the evidence that heavy drinkers cues is associated with higher levels of drug use. endorse positive explicit expectancies but Associative memory tasks present individuals hold negative implicit expectancies (Wiers and with ambiguous words or sentences, which elicit Stacy 2006). Conversely, addicted individuals a free association response that may be related to who enter recovery may find that the opposite drug use. It is hypothesized that repeated experi- holds true; they endorse negative explicit expec- ences with psychoactive drug use leads to the tancies but continue to experience physiological development of specific memory associations arousal and attentional bias, which undermines between the drug of choice and ambiguous cues. their efforts. This dissociation of explicit and Endorsing a greater number of drug-related asso- implicit expectancies may be explained by cogni- ciations predicts heavier drug use (Rooke tive dissonance or self-justification (e.g., “If I use et al. 2008; Wiers and Stacy 2006). the drug, I must enjoy it;” “If I have stopped using the drug, it must be bad”) or may represent internal Harnessing Expectancies for Therapeutic conflict over the decision to engage in substance Change use. Regardless of the mechanism, it appears Expectancies have long been used for therapeutic important to address both types of expectancies change using placebos in medical settings. Place- in efforts to understand or to change substance use. bos can include sugar pills, nontherapeutic doses of medications, therapies that are not empirically Conclusion supported, and medications that have not yet been The decision to use psychoactive substances is proven effective for a specific disorder or popu- influenced by numerous internal and external lation. In relation to psychotropic medication, the factors, including biological, genetic, and social latter is a common occurrence because of the phenomena. Cognitive determinants alone do not number of new drugs available and limited effi- explain substance use; however, it is apparent cacy research, particularly among children and that both explicit and implicit expectancies play adolescents. Research in the past three decades a significant role in the etiology, maintenance, has increasingly focused on finding treatments and cessation of substance use. Given their indi- that surpass placebo effects; however, the utility vidual contributions, both types of expectancies of placebo effects continues to be a source for are necessary in understanding substance use and effecting change. creating effective interventions. Expectancy challenge interventions are designed to identify inaccurate expectancies and provide correct information about the effects of Cross-References drug use. Findings for the efficacy of this intervention have been mixed, although there is evi- ▶ Adolescence and Responses to Drugs dence that expectancy challenges lead to ▶ Attentional Bias to Drug Cues transient reductions in drug use (Jones ▶ Conditioned Drug Effects et al. 2001). Another promising area for reducing ▶ Placebo Effect substance use is strengthening negative ▶ Rodent Tests of Cognition Explicit Expectancies 663 E

References expectancies prior to administration of the substance or placebo. Other procedures provide Earleywine M (ed) (2005) Mind-altering drugs: the sci- either psychoactive drugs or placebos to individ- ence of subjective experience. Oxford University uals in the same group and ask group members to Press, New York Goldman MS, Del Boca FK, Darkes J (1999) Alcohol determine who has received the actual drug. expectancy theory: the application of cognitive neuroscience. In: Leonard KE, Blane HT (eds) Psychologi- cal theories of drinking and alcoholism, 2nd edn. Cross-References Guilford Press, New York, pp 203–246 Hull JG, Bond CF (1986) Social and behavioral conse- ▶ quences of alcohol consumption and expectancy: a Expectancies and Their Inﬂuence on Drug E meta-analysis. Psychol Bull 99:347–360 Effects Jones BT, Corbin WR, Fromme K (2001) A review of expectancy theory and alcohol consumption. Addic- tion 96:57–72 MacAndrew C, Edgerton RB (1969) Drunken comport- ment: a social explanation. Aldine, Oxford Marlatt GA, Rohsenow DJ (1980) Cognitive processes in Expectancy Set alcohol use: expectancy and the balanced placebo design. In: Mello NK (ed) Advances in substance abuse: behavioral and biological research. JAI Press, Definition Greenwich, pp 159–199 Patel AB, Fromme K (2009) Explicit outcome expectan- Expectancy set refers to the belief that cies and substance use: current research and future directions. In: Scheier LM (ed) Handbook of drug a psychoactive substance has been consumed, use etiology. American Psychological Association, regardless of whether or not it has been. During Washington, DC, pp 147–164 experiments designed to evaluate expectancy and Penick SB, Fisher S (1965) Drug-set interaction: pharmacological effects, instructions are given psychological and physiological effects of epinephrine under differential expectations. Psychosom Med that either accurately or incorrectly inform indi- 27:177–182 viduals about whether they received a placebo or Rooke SE, Hine DW, Thorsteinsson EB (2008) Implicit psychoactive substance to activate the cognition and substance use: a meta-analysis. Addict expectancy set. Behav 33:1314–1328 Wiers RW, Stacy AW (eds) (2006) Handbook of implicit cognition and addiction. Sage, Thousand Oaks Cross-References

▶ Expectancies and Their Inﬂuence on Drug Expectancy Challenge Effects

Definition

An expectancy challenge is an intervention designed to provide experimental demonstra- Explicit Expectancies tions of expectancy effects through the use of placebo and active drug effects. Early expec- Definition tancy challenges provided individuals with placebos but stated that they received an active Explicit expectancies are conscious anticipatory drug. After administration, information about cognitions about the effect of some phenomenon. expectancies and their influence on behavior Related to the use of psychoactive substances, was provided. Recent expectancy challenges expectancies describe an individual’s beliefs have used attentional bias to activate about the expected outcomes of consuming the E 664 Externalizing Disorders substance. Explicit expectancies are those that expression of a learned behavioral response. can be deliberately recalled, reflected upon, and In operant conditioning, extinction typically discussed. refers to a procedure that reduces the rate at which a previously acquired ▶ operant response is emitted. The subjects (laboratory animals or Cross-References humans) are first trained to make an operant response (e.g., lever press) to earn ▶ Expectancies and Their Influence on Drug a ▶ reinforcer. Once stable responding is Effects obtained, the reinforcer is no longer presented when the operant response occurs. The number of responses decreases with repeated extinction sessions. Conversely, punished responses are Externalizing Disorders strengthened after a punishing stimulus is withheld. In ▶ Pavlovian (classical) conditioning, Synonyms extinction typically refers to the continued presentation of the ▶ conditioned stimulus with the Disruptive behavior disorders ▶ unconditioned stimulus withheld; this results in a decrease in the magnitude of the ▶ conditioned response across repeated presentations of Definition the conditioned stimulus. Extinction appears not to be the complete erasure or destruction of old Disorders characterized by disinhibited behav- learning, but the acquisition of new learning that iors, such as fighting, bullying, cursing, and competes with or inhibits the expression of the other forms of violence, directed to the external previously learned operant or Pavlovian condi- environment. Examples include attention-deficit/ tioned response. Recent research on extinction hyperactivity disorder, substance use disorders, learning has identified behavioral processes and conduct disorder, pathological gambling, and distinct ▶ neurobiological mechanisms that are kleptomania. Externalizing disorders are often distinct from those responsible for the original diagnosed in late childhood and adolescence, at conditioning, involving active processes of a time when impulsivity is high, contrast to inter- relearning about changed contingencies. nalizing disorders, characterized by disruptions in the ways individuals deal with their emotions. Cross-References

Cross-References ▶ Classical (Pavlovian) Conditioning ▶ Habituation ▶ Attention-Deﬁcit and Disruptive Behavior ▶ Instrumental Conditioning Disorders ▶ Operant Behavior in Animals ▶ Impulse Control Disorders

Extinction of Passive Avoidance Extinction Definition Definition In ▶ instrumental conditioning, the reduction in A process that becomes active in certain situa- the strength of a learned response that occurs tions and that leads to a reduction in the because the response is no longer reinforced. Extracellular Recording 665 E

In passive avoidance, extinction refers to the to another of the CNS. Extracellular recordings gradually shorter transfer latency to enter the represent a very powerful technique for investi- dark compartment upon retesting because the gating the function within CNS pathways, since it initially punished transfer into the dark compart- provides both high-resolution information from ment is not paired with the ▶ negative reinforcer neural tissue in vivo and in vitro and information (US) anymore. Conceptually, extinction memory on the spiking (output) and synaptic activity is formed that competes with the original mem- (input) of neurons in a particular recorded area. ory to suppress the initial fear memory. Paired with our understanding of anatomy, recordings can reveal information on the input–output function in neuronal networks. E In comparison, intracellular recordings and Extracellular Recording patch-clamp recordings, by their very nature, produce short lasting recordings of underlying Victoria L. Harvey and Anthony H. Dickenson events such as EPSPs (excitatory postsynaptic Neuroscience, Physiology and Pharmacology, potentials), IPSPs (inhibitory postsynaptic poten- University College London, London, UK tials), and channel activity, whereas extracellular recordings can provide hours of recording, rendering the approach suitable for examining both Synonyms detailed response characteristics and also pharmacological manipulations. The patterns of activ- Measurement of neuronal activity ity can be viewed and monitored in real time, and so extracellular activity allows neuronal function to be studied in normal conditions and then be Definition compared with pathological or dysfunctional states neuronal activity. Changes in neuronal Extracellular recordings are used to monitor neu- activity in response to pharmacological manipu- ronal activity from outside the cell. It provides lation can also be assessed. Importantly, neuronal a means to measure patterns of action potentials activity provides an objective and unbiased way within many areas of the peripheral and central of observing changes in neuronal systems and nervous systems. In addition, massed activity can these quantitative measures of firing of a neuron also be recorded. The effects of pathology and are less subjective than a behavioral response. drugs can be investigated over extended time The general principle of extracellular record- courses using this technique. ings involves detecting the changes in the membrane potential of neurons, which occur during the firing of action potentials. Differences in the Principles and Role in voltage fluctuations between the recording elec- Psychopharmacology trode (placed in the target tissue) and a reference wire (placed at a more distal site) are recorded. Principles of Extracellular Recording The firing of action potentials requires the tran- Richard Caton (1842–1926), who performed sient opening of a sodium channel, and since electroencephalography (EEG) from the surface the concentration of sodium is greater outside of of living brains in animals, first discovered the the neuron than inside, the sodium flows down electrical nature of the brain (Caton 1875). These its concentration gradient. This reduction of electrical impulses, in the form of action poten- positive ions from the extracellular environment tials, underlie the information processing capa- is observed as a negative voltage fluctuation bilities of the central nervous system (CNS). The with respect to the reference electrode. Com- pattern, frequency, and coding of this activity monly, these signals are small (<1 mV) and allows messages to be transferred from one area require signal amplification, and filtering with E 666 Extracellular Recording low- (<1 Hz) and high-pass (>3 kHz) filters, to with time may be issues. In most studies of this produce a useful measurable output. Therefore, nature, the animals will be placed in a stereotaxic extracellular recording allows responses to be frame to maintain stability at the recording site recorded and quantified as a result of controlled during electrophysiological recordings and allow sensory or electrical stimulation, used either as for defined brain areas to be located using coor- a means of activating neurons in one area to dinates found in a stereotaxic atlas; the placement identify functional connections or as of the electrode is confirmed histologically at the a conditioning stimulus or even simple ongoing end of the experiment. activity. Once these responses have been mea- Electrodes of many types can be used, ranging sured, it is then possible to apply drugs by from glass to parylene-coated tungsten. The ways a wide range of routes, namely, systemic, local in which action potentials or other forms of activ- (icv, by microinjection or spinal), or directly to ity are monitored and measured are varied, but in the neuron. general terms a head stage will receive input from Drugs can be used as agonists to activate either the recording electrode, and often differential excitatory or inhibitory receptors, using their recordings are made where activity from the mus- effects on action potentials as a measure of the cle, cardiovascular, and respiratory systems as existence of that receptor in the particular circuit. well as an eventual electrical interference, from Antagonist studies, however, are likely to be the the surrounding environment, is subtracted from most powerful, since the physiological activation the main input. Efficient grounding of the record- of a particular receptor, by release of the endog- ing system is necessary for high signal-to-noise enous transmitter in the pathway under study, can recordings. be evidenced by the ability of a drug that blocks Equipment is needed to amplify and differen- a receptor to alter activity in the neuron. This type tiate the input, to allow filtering between defined of study can further be used to study the potential frequencies, and often the signal is monitored by changes in transmitter systems in pathophysio- both audible and then visible means on an oscil- logical events by comparing responses between loscope. Neurones are differentiated according to control and experimental groups. In this context, their amplitude by use of a window discriminator care is needed to ensure that similar populations with adjustable window height, to separate activ- of neurons are recorded in both groups to allow ity from the baseline background noise or to valid comparisons. In a similar way, the same discriminate a single neuron based on waveform measures can be made in wild-type and trans- and amplitude. The activity is then quantified and genic mice to allow functional roles of protein further analyzed, mostly online by use of an products to be ascertained in situations where interface linked to a computer, where the cap- pharmacological tools are lacking or insuffi- tured data is quantified, analyzed, and displayed ciently selective. using software. The ability to monitor action potentials in Technical Considerations a dynamic fashion can be used in many ways. Extracellular activity is most often recorded The recording of single unit activity allows an in vivo under anesthesia throughout the study unequivocal measure of the integrated responses or, in the case of activity in unrestrained animals, of a single neuron, but mass activity of neuronal have a recording device secured in place under populations can also be measured as field poten- surgical anesthesia. In the former case, volatile tials or multiunit recordings, and activity of more anesthetics such as isoflurane or halothane, often than one single unit in an area can be measured delivered in a gaseous mixture of N2O:O2, are simultaneously using electrode arrays. used, with anesthesia maintained at a steady state throughout the recording period. Other Single-Unit Recordings approaches use urethane, pentobarbitone, etc., In vivo extracellular recordings can be performed as anesthetics, but here fluctuations in levels with relatively little damage to the surrounding Extracellular Recording 667 E tissue. Single-unit recordings using an electrode specific location, were first described (O’Keefe with a small tip (<1 mm, microelectrode) can be and Dostrovsky 1971). This technique can be used to monitor the electrical activity of a single used to both observe the synchronized activity cell. Neuronal activity is recorded once the of the neurons, within the locality of the record- microelectrode is positioned in proximity to ing electrode and identify the number and type of a neuron. Current fields, generated by action cells responding to the stimulus in different brain potentials, are detected through the tip of areas. This process is known as spike sorting, a microelectrode and are displayed as small volt- where the time course of a particular spike is age deflections occurring in the millisecond defined by the size and shape of a neuron and its range. Stimulation can be used to measure the position relative to the recording electrode. Anal- E postsynaptic effects of an afferent input to ysis based solely on changes in amplitude can be a neuron. Electrical pulses are applied to difficult to interpret as neurons are physiologi- a stimulating electrode to activate neurons that cally heterogeneous, such that the activity in one project to where a target cell is recorded. For neuron may cancel out the activity in an opposing example, tungsten microelectrodes positioned in neuron. Thus, more sophisticated algorithms the dorsal horn of the spinal cord of rats, in an have been developed to separate and identify area receiving information from the hindpaw, can the activity produced by each individual neuron be used to measure the activity of second-order in the local vicinity. neurons receiving both afferent information from In vivo recordings permit recordings from the periphery and descending modulation from intact neuronal networks; however, it may be the brain (Urch and Dickenson 2003). Neuronal difficult to gain access to certain target structures. activity is recorded in response to a wide range of Recordings from in vitro studies, therefore, can stimuli applied at the periphery. Typically, be used to provide information from such areas poststimulus time histograms (PSTHs) summat- and avoid any potential problems associated with ing neuronal activity from a series of trials are anesthesia. In vitro electrophysiology can be compiled, allowing the measurement of even rel- performed on cell cultures, acute or cultured tis- atively weak responses. Together with pharma- sue slices, and isolated superfused structures cology, this approach can be used to investigate (e.g., brainstem). Acutely isolated neurons, by the mechanisms involved in the transmission and mild enzymatic digestion of brain slices, and processing of nociceptive information, for exam- cultured neurons offer advantages over in vivo ple (Suzuki et al. 2002). preparations, as they allow direct visualization using a microscope. The administration of Multi-unit Recordings ligands of defined concentrations can be applied By increasing the diameter of the recording elec- rapidly and repeatedly, and molecular targets can trode or by using multielectrode arrays, multi- be isolated by pharmacological manipulation unit recordings can be performed measuring the using agents known to block undesired systems. activity of several neurons simultaneously. However, these preparations lack the integrity of Multi-unit recordings are often performed in con- network interconnectivity and are devoid of the scious freely moving animals and can provide long-range targets that are present in in vivo information on integrated systems facilitating recordings. the understanding of the transformation of sen- Similar to in vivo recordings, in vitro record- sory input to its functional behavioral output. ings can be performed extracellularly (as well as Normally, the animals have been trained for intracellularly). Because of the small signal, neu- a particular behavior and the aim is to look for ronal activity is often obtained using multi-unit a neuronal correlate to this behavior. This recordings (field potentials) observing changes in approach has proved particularly successful in the potentials of the neurons with respect to the the hippocampus where “place cells,” which recording electrode, visualized as a change in exhibit high-frequency firing in response to amplitude. The activity of individual neurons E 668 Extracellular Recording cannot be distinguished; rather the activity of provides information regarding the reuptake and a group of neurons is recorded as a field potential. metabolism of transmitters and vesicle release This approach has been employed with great probability but is limited to those cells that success in understanding the role of the hippo- secrete a detectable substance. More recently, campus. For instance, the concept that learning this technique has been developed by pairing it and memory might be underpinned by persistent with other types of electrophysiology such as changes in the strength of synaptic contacts patch clamping (patch amperometry) allowing within the hippocampus, a structure with clearly the simultaneous determination of the fusion defined pathways, laminae, and circuits, was pore conductance, vesicle size, and the kinetics borne out by the ability to activate a large number of transmitter release from the same vesicle. of synapses using an extracellular stimulator Fluorescence imaging is also employed, tagging (e.g., perforant path) and record large responses proteins involved in the exocytotic machinery, of many cells simultaneously with an extracellu- thus allowing the investigation of the spatiotem- lar electrode placed in another area such as the poral dynamics of neurotransmission and secre- granule cell layer or pyramidal layer (Bliss and tion. Further advances have been made in the Lømo 1973). This paved the way for the numer- form of multi-electrode arrays (MEAs) to study ous studies of synaptic activity related to plastic- exocytotic events from multiple sites avoiding ity in the brain, with long-term potentiation problems with micromanipulation, and this strat- (LTP) being the key proposed mechanism in egy has proved useful in the understanding of this regard. neuronal communication in brain slices, neuronal cultures, and has been used in drug discovery. Carbon Fiber Amperometry Carbon fiber amperometry can be used to investigate exocytosis of neurotransmitters and hor- Cross-References mones from presynaptic neurons and other secretory cells. Much of our current understand- ▶ Analgesics ing of vesicular fusion and subsequent transmitter ▶ Event-Related Potential release has been gained by amperometric record- ▶ Intracellular Recording ings (either alone or in combination with other ▶ Long-Term Potentiation and Memory techniques), such as the identification of the ▶ Synaptic Plasticity fusion pore (the initiating event of exocytosis), kiss-and-run fusion (fast vesicle recycling), and the understanding of the interplay between vari- References ous parts of the synaptic machinery (e.g., Alvarez de Toledo G, Fernández-Chacoń R, Fernández Munc18-1/syntaxin) (Chow et al. 1992; Neher JM (1993) Release of secretory products during tran- 1993). sient vesicle fusion. Nature 363(6429):554–558 The general principle involved relies on the Bliss T, Lømo T (1973) Long-lasting potentiation of syn- measurement of amperometric spikes resulting aptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the from the electrochemical current elicited by the perforant path. J Physiol 232(2):331–356 oxidation and reduction of certain molecules. Caton R (1875) The electric currents of the brain. Br Med This can be measured by placing a carbon fiber J 2:278 € electrode held at a constant potential Chow RH, von Ruden L, Neher E (1992) Delay in vesicle fusion revealed by electrochemical monitoring of sin- (amperometry) or cycling (voltammetry) close gle secretory events in adrenal chromaffin cells. to the cell of interest. Certain neurotransmitters Nature 356(6364):60–63 (viz., monamines and catecholamines) lose Neher E (1993) Cell Physiology. Secretion without full (oxidation) or gain (reduction) electrons at char- fusion. Nature 363(6429):497–498 O’Keefe J, Dostrovsky J (1971) The hippocampus as acteristic voltages, allowing the identification of a spatial map. Preliminary evidence from unit activity particular brain chemicals. This approach in the freely-moving rat. Brain Res 34:171–175 Eye Movement Tasks 669 E

Suzuki R, Morcuende S, Webber M, Hunt SP, Dickenson involved in the coordination of movement. Extra- AH (2002) Superﬁcial NK1-expressing neurons con- pyramidal symptoms refer most commonly to the trol spinal excitability through activation of descending pathways. Nat Neurosci 5(12):1319–1326 side effects of many antipsychotics that affect Urch CE, Dickenson AH (2003) In vivo single unit extra- movements. They include neurologic syndromes cellular recordings from spinal cord neurones of rats. such as dystonia, dyskinesia, and Parkinson-like Brain Res Brain Res Protoc 12(1):26–34 disturbances including tremor, rigidity, and bradykinesia as well as akathisia. These adverse events can occur both during acute and the Extradimensional chronic treatment with antipsychotics. They are sequelae of the dopamine antagonist properties of E Synonyms antipsychotics. In general, they are dose- dependent and more severe and frequent with ED ﬁrst-generation antipsychotics than with the newer drugs.

Definition Cross-References In the context of an ID/ED task, the extradimensional (ED) stage involves discriminat- ▶ Antipsychotic Drugs ing between two (generally novel) stimuli that dif- ▶ First-Generation Antipsychotics fer from each other in at least two dimensions (e.g., ▶ Movement Disorders Induced by Medications color and shape) but for which the relevant discrim- ▶ Tardive Dyskinesia inative dimension (e.g., shape) is unattended because the irrelevant dimension (e.g., color) has been primed by prior experience. In the ID/ED task, the critical comparison is between the ID Eye Movement Tasks and ED stages: although both are formally novel acquisitions, prior experience biases attention such Samuel B. Hutton that there is a beneﬁt of ID over ED acquisition. Department of Psychology, University of Sussex, Falmer, Brighton, UK

Cross-References Synonyms ▶ Behavioral Flexibility: Attentional Shifting, Rule Switching, and Response Reversal Eye tracking; Oculomotor tasks; Saccades; Smooth pursuit

Extrapyramidal Motor Side Effects Definition Synonyms Eye movement tasks are a powerful tool with EPS which researchers can study the effects of pharmacological compounds on brain function. Although there are several different classes of Definition eye movements (see Leigh and Zee 2006), two types are particularly relevant to psychopharma- The extrapyramidal system is a neural network cological research. Saccadic eye movements are located in the central nervous system, which is rapid, conjugate movements of the eyes, which E 670 Eye Movement Tasks serve to orient the high acuity foveal region of the prosaccade task, participants typically fixate retina onto a specific region of visual space. a central stimulus (such as a small cross) for Smooth pursuit involves slower eye movements a short period of time and then make a saccade that serve to keep an object foveated if it moves towards a sudden onset target which appears in across our field of vision. Both saccades and the left or right hemifield. Key metrics include the smooth pursuit eye movements are influenced latency of the saccade (e.g., its reaction time with by endogenous factors, such as our goals and respect to the target onset), its amplitude, dura- expectations, as well as exogenous factors, such tion, and peak velocity. In a standard smooth as the size, shape, and luminance of an object in pursuit, task participants are asked to follow the visual field, and as such can provide important a moving target (typically a small circle) with insights into the effects of pharmacological com- their eyes. The target moves backwards and for- pounds on cognitive function. In addition, eye wards along the horizontal axis, with either movements made to more complex stimuli, such a constant or sinusoidal velocity. Key metrics as faces or scenes, can also reveal important include pursuit velocity gain (the ratio of the information concerning cognitive function. eye velocity to target velocity) and the number of saccades made during pursuit. Reductions in pursuit velocity gain are typically compensated Principles and Role in for by an increase in the number of corrective Psychopharmacology “catch-up” saccades. The prosaccade task seems, on the surface, to The use of eye movement tasks as a tool with require very little in the way of cognitive which to investigate the effects of pharmacolog- processing, but the average prosaccade latency ical interventions on brain function has a number (190 ms) is around 100 ms longer than would of distinct advantages. Firstly, sophisticated eye be required if the response was simply a reflex. It tracking technology means that eye movements has been argued that this extra time reflects can now be measured with exceptional accuracy a “decision” process – our brain needs to deter- and reliability. Secondly, the neural systems mine not just where to look but whether it is involved in eye movement control have been worth looking there at all. This decision reflects well established by neurophysiological studies the influences of both exogenous (bottom-up) and in nonhuman primates and lesion studies in endogenous (top-down) factors and is clearly humans – it has been argued that the oculomotor related to the processes that determine where we system provides researchers with a “microcosm allocate our attention. The precise nature of the of the brain” (Carpenter 1994). Thirdly, the neu- relationship between saccades and visual atten- ral systems involved in eye movement control tion remains a topic of considerable debate, but overlap considerably with those that mediate there is agreement that the neural mechanisms important cognitive processes such as those underpinning them overlap considerably. Fol- involved in attention and working memory, and lowing a target as it moves horizontally also the simplicity of eye movement tasks enables seems to require relatively little in terms of cog- them to be manipulated in ways that allow spe- nitive effort. Again, though, research has demon- cific cognitive processes to be isolated. Finally strated that smooth pursuit eye movements pharmacological compounds have been shown to involve a surprisingly complex set of information have replicable effects on a range of eye processing stages, including the generation of an movements. internal model of the target’s velocity. Other eye movement tasks that have a more Eye Movement Tasks obvious “cognitive” involvement are increas- The majority of research into the effects of phar- ingly being used in psychopharmacological macological compounds on eye movement func- research. These tasks typically place a greater tion has used two very simple paradigms. In the role on higher cognitive functions than the Eye Movement Tasks 671 E prosaccade and smooth pursuit tasks described standard tasks of cognitive function. In the above. The antisaccade task is an important var- dot-probe task, for example, two images are iant of the prosaccade task. The stimulus timings presented simultaneously for a short period of and properties are identical in the two tasks, but time, and participants’ reaction time to a dot in the antisaccade task, participants are instructed that appears subsequently behind one or the to saccade to the mirror image location of the other is measured. The task is typically used to sudden onset target rather than towards it. The measure attentional biases (e.g., towards drug- task thus requires participants to inhibit a highly related stimuli in a drug addict) but can also be prepotent response (to saccade towards the sud- used to index potentially subtle effects of psycho- den onset target) and initiate an internally gener- pharmacological compounds on specific types of E ated response (to saccade to the mirror image information processing – for example, whether location). Many neuropsychological tasks sensi- alcohol biases attention towards negative or pos- tive to damage to the prefrontal cortex (e.g., itive facial expressions. Recording eye move- Stroop) share this requirement to respond on ments during dot-probe performance allows basis of an internal goal as opposed to an external variables such as the time to first fixation, first stimulus, and patients with lesions to this area, as fixation duration, and total dwell time for each of well as patients with psychiatric disorders such as the images to be measured. These measures can schizophrenia, in which prefrontal dysfunction is potentially reveal subtle effects of pharmacolog- implicated, make a large number of antisaccade ical compounds that a simple reaction time mea- errors (prosaccades made towards the target). sure may be insensitive to. The key metric of the antisaccade task is the proportion of trials in which antisaccade errors Eye Tracking Techniques occur. However, the latency, amplitude, and Eye movements can be recorded using a variety velocity of correct antisaccades can also be of techniques (see Duchowski 2007 for informative. a comprehensive discussion). Early research There are other simple eye movement tasks mainly used electrooculography, in which pairs that are routinely used in other research settings of electrodes placed near the eye record small but which have yet to be widely adopted in psy- changes in voltage that occur as it moves. Most chopharmacological studies. These include current eye trackers are video based and use high- remembered and predictive saccades and predic- speed cameras and sophisticated image analysis tive pursuit. Eye movement tasks that use more systems to establish the location of the pupil and complex stimuli are also potentially informative the corneal reflection of an infrared light source. and can also exploit the close relationship After a simple calibration procedure, the vector between eye movements and attention. For exam- between these two points can be used to deter- ple, in visual search tasks, participants are mine the location of gaze. In some eye tracking required to identify one or more target items systems, the camera recording the eye movement (e.g., the letter “L”) presented in an array of is mounted on a lightweight headset, but increas- distractors (e.g., the letter “T”). Standard visual ingly remote optics are being used, with fixed search tasks provide a single measure – reaction cameras placed beneath the monitor on which time. When combined with eye tracking, how- stimuli are displayed. ever, metrics such as the number of refixations on previously identified targets or the average angle Eye Movement Tasks in between saccades can provide important infor- Psychopharmacological Research mation concerning the functionality of working There are two broad areas of psychopharmaco- memory and attentional processes and the high logical research in which eye movement tasks level strategies participants are using to perform have been widely used: (1) investigations the task. Eye tracking can also be used to provide into the acute effects of pharmacological com- important insights into performance on other pounds on psychological functioning in healthy E 672 Eye Movement Tasks participants and (2) investigations into the more found to decrease prosaccade peak velocity and chronic effects of pharmacological treatments in disrupt smooth pursuit performance. In both clinical (typically psychiatric) populations. Evi- cases, the effects likely reflect the sedative prop- dence from these two fields of research will be erties of these compounds on CNS function. The considered separately. A very thorough treatment effects of second-generation antipsychotics on of both literatures is provided by Reilly et al. eye movement tasks have not been well (2008). established, although reductions in prosaccade velocity have again been observed. Acute Effects in Healthy Participants Stimulants, such as amphetamines and cholin- The majority of studies into the acute effects of ergic agonists like nicotine, do not appear to pharmacological compounds on eye movements improve performance on standard prosaccade or have been done in the context of tolerability smooth pursuit tasks, possibly because perfor- studies. A number of different psychopharmaco- mance on these simple tasks is typically already logical compounds have been shown to have rep- optimal. Interestingly, SSRIs and 5HT agonists licable effects on eye movements. Early research have been found to impact on some eye move- established clear dose-dependent relationships ment metrics – most notably resulting in between serum concentrations of benzodiaze- increases in saccade peak velocity and pursuit pines such as diazepam and temazepam and sac- velocity gain. The underlying mechanism by cade peak velocity – saccade velocity decreases which these improvements are mediated is not as serum concentration of benzodiazepines clear (they do not appear to reflect an increase increases. These effects are presumably mediated in alertness), but there are known serotonergic via GABAergic connections between the caudate pathways in brain stem regions involved in sac- nucleus and the substantia nigra pars reticulata cade generation. and between the nigra and the superior Despite the well-established effects of benzo- colliculus – both regions that lesion studies have diazepines and antipsychotics on prosaccade and confirmed are critical for the generation of sac- smooth pursuit function, comparatively few stud- cades. The clear relationship between saccade ies have explored the effects of these compounds velocity and benzodiazepine dose led to the use on antisaccade performance or other eye move- of eye movement tasks as an index of the sedative ment tasks requiring greater attentional and cog- effects of psychopharmacological compounds. nitive control. In one study lorazepam, but not Recent studies have confirmed that saccade chlorpromazine, was found to increase velocity is more sensitive to the sedative effects antisaccade error rate (although not, surprisingly, of benzodiazepines than other common measures antisaccade velocity). A larger number of studies of alertness such as rating scales or measures of have explored the effects of nicotine on psychomotor speed. Benzodiazepines also have antisaccade performance in healthy participants. consistent effects on smooth pursuit velocity. Several studies have found that nicotine can Again studies have demonstrated a dose- increase correct antisaccade latencies and dependent relationship such that increases in reduces the number of antisaccade errors. Nico- serum concentration of benzodiazepine are asso- tine has also been found to improve performance ciated with a reduction in smooth pursuit velocity on visual search tasks in smokers, resulting in gain and consequent increase in the number of a reduction in the number of fixations on nontar- corrective “catch-up” saccades. get items. Other pharmacological compounds, in particular first-generation antipsychotics, whose pri- Treatment Effects in Patient Populations mary action is the blockade of dopamine As Reilly et al. (2008) note, given the potential receptors and anticonvulsant/mood-stabilizing advantages outlined earlier, it is perhaps surpris- compounds such as lithium, have also been ing that the literature examining the effects of Eye Movement Tasks 673 E medication on eye movement function in patients have been shown to slightly ameliorate impair- with clinical disorders is comparatively limited. ments in smooth pursuit and antisaccade perfor- While medication is often included as a factor in mance in patients with schizophrenia. In contrast, studies that have measured eye movement func- anticholinergic compounds such as procyclidine tion in clinical populations, longitudinal random- have been found to impair performance on these ized designs (which would allow direct tasks in this population. inferences concerning the effects of different The evidence concerning the effects of medi- medications on oculomotor function) are rare. In cation on eye movements in other disorders is addition, methodological differences between sparse and often contradictory. There is no con- studies with respect to the eye movement tasks sensus as to the effects of stimulants such as E used make comparisons difficult. The effects of methylphenidate on eye movement task perfor- psychiatric and neurological disorders them- mance in patients with attention deficit hyperac- selves (as opposed to medication effects) are tivity disorder (ADHD). Some, but not all, studies reviewed comprehensively elsewhere. have found that treatment with dopamine ago- The effects of first- and second-generation nists improves performance on some eye move- antipsychotics on eye movement performance in ment tasks in patients with Parkinson’s disease. patients with schizophrenia are perhaps the best characterized. In accordance with the findings of Limitations single-dose studies in healthy participants, first- While one of the potential advantages of basic and second-generation antipsychotics have been eye movement tasks such as prosaccades and found to reduce prosaccade velocity in patients smooth pursuit is their simplicity, there are with schizophrenia. Antipsychotic medications a myriad of methodological variations in the also result in a reduction in prosaccade ways in which these tasks are presented. It is amplitude – hypometria. This hypometria is par- becoming increasingly clear that small differ- ticularly pronounced for endogenously generated ences in apparently minor details such as the saccades, such as occur in the remembered sac- size of the target, its distance from the central cade task (in which participants initiate a saccade fixation point, or its temporal relationship with to a location based on their memory for where the the offset of the central fixation stimulus can all target stimulus appeared) and the predictive sac- have a significant impact on metrics such as saccade task (in which participants saccade to cade latency and amplitude. These differences a target moving backwards and forwards between considerably complicate cross study compari- two locations at a predictable frequency). Inter- sons. The situation is perhaps even more serious estingly saccade hypometria is a feature of for more “cognitive” eye movement tasks such as patients with Parkinson’s disease and thus may antisaccades, in which differences in the way reflect decreased striatal dopamine availability. instructions are given have been shown to have Performance on the antisaccade task does not an impact on the number of errors made (see appear to be effected by antipsychotic treatment, Hutton 2008). despite improvement in neuropsychological indices of cognitive function that can occur with Future Directions treatment. Another important finding is that stud- There have been comparatively few investiga- ies investigating changes in psychotic symptoms tions into the effects of pharmacological com- and eye movements as a result of treatment initi- pounds on variations on the standard eye ation in previously antipsychotic free patients movement tasks, such as the antisaccade task have found that changes in both over time are and predictive smooth pursuit. Even fewer stud- unrelated. ies have attempted to use eye tracking to explore Interestingly, mirroring their beneficial effects the effects of pharmacological interventions on in healthy participants, nicotinic compounds eye movements made to more complex stimuli E 674 Eye Movement Tasks

(such as scenes or faces) or more complex tasks provide researchers with important insights into (such as visual search or matching familiar fig- the mechanisms through which pharmacological ures tests). Future research using these more compounds impact on cognitive function. complicated tasks, and related tasks that exploit the link between gaze and endogenous attentional processes, may provide important insights into Cross-References the effects of pharmacological compounds on brain function. ▶ Antidepressants Another important use of eye movement tasks ▶ Antipsychotic Drugs in the future will be in pharmacogenetic studies. ▶ Benzodiazepines Researchers have already employed eye move- ▶ Decision Making ments as intermediate phenotypic markers of ▶ Executive Functions schizophrenia in family genetic studies. In addi- ▶ First-Generation Antipsychotics tion, several studies have established relation- ▶ Nicotine ships between genotype and oculomotor ▶ Pharmacogenetics function in patients with schizophrenia – for ▶ Psychomotor Performance in Humans example, male patients with the Met/Met allele ▶ Schizophrenia of the catechol-o-methyltransferase (COMT) Val/Met polymorphism had significantly better smooth pursuit performance compared to patients References with other genotypes. Other research has found that the sensitivity of smooth pursuit velocity Carpenter RHS (1994) Choosing where to look. Curr Biol gain to benzodiazepines is moderated by 4:341–343 genotype – carriers of the Ser385 allele, associ- Duchowski A (2007) Eye tracking methodology: theory and practice. Springer, New York ated with alcoholism, demonstrated a smaller Hutton SB (2008) Cognitive control of saccadic eye benzodiazepine-induced reduction in pursuit movements. Brain Cogn 68:327–340 velocity gain than noncarriers. Such finding sug- Leigh RJ, Zee DS (2006) The neurology of eye move- gest that basic eye movement tasks such as ments. Oxford University Press, Oxford Reilly JL, Lencer R, Bishop JR, Keedy S, Sweeney JA prosaccade and smooth pursuit, as well as more (2008) Pharmacological treatment effects on eye complex eye movement tasks, will continue to movement control. Brain Cogn 68:415–435