Showing papers in "Psychopharmacology in 2007"

The debate over dopamine’s role in reward: the case for incentive salience

Abstract: Introduction Debate continues over the precise causal contribution made by mesolimbic dopamine systems to reward. There are three competing explanatory categories: ‘liking’, learning, and ‘wanting’. Does dopamine mostly mediate the hedonic impact of reward (‘liking’)? Does it instead mediate learned predictions of future reward, prediction error teaching signals and stamp in associative links (learning)? Or does dopamine motivate the pursuit of rewards by attributing incentive salience to reward-related stimuli (‘wanting’)? Each hypothesis is evaluated here, and it is suggested that the incentive salience or ‘wanting’ hypothesis of dopamine function may be consistent with more evidence than either learning or ‘liking’. In brief, recent evidence indicates that dopamine is neither necessary nor sufficient to mediate changes in hedonic ‘liking’ for sensory pleasures. Other recent evidence indicates that dopamine is not needed for new learning, and not sufficient to directly mediate learning by causing teaching or prediction signals. By contrast, growing evidence indicates that dopamine does contribute causally to incentive salience. Dopamine appears necessary for normal ‘wanting’, and dopamine activation can be sufficient to enhance cue-triggered incentive salience. Drugs of abuse that promote dopamine signals short circuit and sensitize dynamic mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Such drugs interact with incentive salience integrations of Pavlovian associative information with physiological state signals. That interaction sets the stage to cause compulsive ‘wanting’ in addiction, but also provides opportunities for experiments to disentangle ‘wanting’, ‘liking’, and learning hypotheses. Results from studies that exploited those opportunities are described here.

Tonic dopamine: opportunity costs and the control of response vigor.

Abstract: Rationale Dopamine neurotransmission has long been known to exert a powerful influence over the vigor, strength, or rate of responding. However, there exists no clear understanding of the computational foundation for this effect; predominant accounts of dopamine’s computational function focus on a role for phasic dopamine in controlling the discrete selection between different actions and have nothing to say about response vigor or indeed the freeoperant tasks in which it is typically measured. Objectives We seek to accommodate free-operant behavioral tasks within the realm of models of optimal control and thereby capture how dopaminergic and motivational manipulations affect response vigor. Methods We construct an average reward reinforcement learning model in which subjects choose both which action to perform and also the latency with which to perform it. Optimal control balances the costs of acting quickly against the benefits of getting reward earlier and thereby chooses a best response latency. Results In this framework, the long-run average rate of reward plays a key role as an opportunity cost and mediates motivational influences on rates and vigor of responding. We review evidence suggesting that the average reward rate is reported by tonic levels of dopamine putatively in the nucleus accumbens. Conclusions Our extension of reinforcement learning models to free-operant tasks unites psychologically and computationally inspired ideas about the role of tonic dopamine in striatum, explaining from a normative point of view why higher levels of dopamine might be associated with more vigorous responding.

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits.

Abstract: Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation.

Guidelines on nicotine dose selection for in vivo research

Abstract: Rationale This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.

The nucleus accumbens as part of a basal ganglia action selection circuit.

Abstract: The nucleus accumbens is the ventral extent of the striatum, the main input nucleus of the basal ganglia. Recent hypotheses propose that the accumbens and its dopamine projection from the midbrain contribute to appetitive behaviors required to obtain reward. However, the specific nature of this contribution is unclear. In contrast, significant advances have been made in understanding the role of the dorsal striatum in action selection and decision making. In order to develop a hypothesis of the role of nucleus accumbens dopamine in action selection, the physiology and behavioral pharmacology of the nucleus accumbens are compared to those of the dorsal striatum. Three hypotheses concerning the role of dopamine in these structures are proposed: (1) that dopamine release in the dorsal striatum serves to facilitate the ability to respond appropriately to temporally predictable stimuli (that is, stimuli that are so predictable that animals engage in anticipatory behavior just prior to the stimulus); (2) that dopamine in the nucleus accumbens facilitates the ability to respond to temporally unpredictable stimuli (which require interruption of ongoing behavior); and (3) that accumbens neurons participate in action selection in response to such stimuli by virtue of their direct (monosynaptic inhibitory) and indirect (polysynaptic excitatory) projections to basal ganglia output nuclei.

Linking nucleus accumbens dopamine and blood oxygenation.

Abstract: Animal research suggests that anticipation of reward can elicit dopamine release in the nucleus accumbens (NAcc). Human functional magnetic resonance imaging (FMRI) research further suggests that reward anticipation can increase local blood oxygen level dependent (BOLD) signal in the NAcc. However, the physiological relationship between dopamine release and BOLD signal increases in the NAcc has not yet been established. This review considers pharmacological MRI (phMRI) evidence for a directional relationship between NAcc dopamine release and BOLD signal, as well as implications for human psychopathological symptoms. Accumulating phMRI evidence supports a simple model in which NAcc dopamine release activates postsynaptic D1 receptors, which changes postsynaptic membrane potential, eventually increasing local BOLD signal. This continuing influence can change on a second-to-second basis. Dopamine release in the NAcc appears to increase local BOLD signal via agonism of postsynaptic D1 receptors. Such a physiological mechanism implies that FMRI may be used to track symptoms related to NAcc dopaminergic dysregulation in psychiatric disorders including schizophrenia and attention deficit/hyperactivity disorder.

Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding

Abstract: Background and objectives The idea that nucleus accumbens (Acb) dopamine transmission contributes to the neural mediation of reward, at least in a general sense, has achieved wide acceptance. Nevertheless, debate remains over the precise nature of dopamine’s role in reward and even over the nature of reward itself. In the present article, evidence is reviewed from studies of food intake, feeding microstructure, instrumental responding for food reinforcement, and dopamine efflux associated with feeding, which suggests that reward processing in the Acb is best understood as an interaction among distinct processes coded by discrete neurotransmitter systems.

Functional MRI of inhibitory processing in abstinent adolescent marijuana users

Abstract: Background Marijuana intoxication appears to impair response inhibition, but it is unclear if impaired inhibition and associated brain abnormalities persist after prolonged abstinence among adolescent users. We hypothesized that brain activation during a go/no-go task would show persistent abnormalities in adolescent marijuana users after 28 days of abstinence.

Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats

Abstract: The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders. We studied individual differences in Pavlovian conditioned approach behavior and examined the expression of neurobiological markers associated with the dopaminergic system, the same neural system implicated in incentive motivational processes. Pavlovian autoshaping procedures consisted of the brief presentation of an illuminated retractable lever (conditioned stimulus) followed by the response-independent delivery of a food pellet (unconditioned stimulus), which lead to a Pavlovian conditioned response. In situ hybridization was performed on brains obtained either following the first or last (fifth) day of training. Two phenotypes emerged. Sign-trackers (ST) exhibited behavior that seemed to be largely controlled by the cue that signaled impending reward delivery; whereas goal-trackers (GT) preferentially approached the location where the reward was delivered. Following a single training session, ST showed greater expression of dopamine D1 receptor mRNA relative to GT. After 5 days of training, GT exhibited greater expression levels of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor mRNA relative to ST. These findings suggest that the development of approach behavior towards signals vs goal leads to distinct adaptations in the dopamine system. The sign-tracker vs goal-tracker phenotype may prove to be a valuable animal model to investigate individual differences in the way incentive salience is attributed to environmental stimuli, which may contribute to the development of addiction and other compulsive behavioral disorders.

Profile of executive deficits in cocaine and heroin polysubstance users: common and differential effects on separate executive components.

Abstract: Structure of executive function was examined and we contrasted performance of substance dependent individuals (polysubstance users) and control participants on neuropsychological measures assessing the different executive components obtained. Additionally, we contrasted performance of polysubstance users with preference for cocaine vs heroin and controls to explore possible differential effects of the main substance abused on executive impairment. Two groups of participants were recruited: abstinent polysubstance users and controls. Polysubstance users were further subdivided based on their drug of choice (cocaine vs heroin). We administered to all participants a comprehensive protocol of executive measures, including tests of fluency, working memory, reasoning, inhibitory control, flexibility, and decision making. Consistent with previous models, the principal component analysis showed that executive functions are organized into four separate components, three of them previously described: updating, inhibition, and shifting; and a fourth component of decision making. Abstinent polysubstance users had clinically significant impairments on measures assessing these four executive components (with effect sizes ranging from 0.5 to 2.2). Cocaine polysubstance users had more severe impairments than heroin users and controls on measures of inhibition (Stroop) and shifting (go/no go and category test). Greater severity of drug use predicted poorer performance on updating measures. Executive functions can be fractionated into four relatively independent components. Chronic drug use is associated with widespread impairment of these four executive components, with cocaine use inducing more severe deficits on inhibition and shifting. These findings show both common and differential effects of two widely used drugs on different executive components.

Compulsive drug seeking by rats under punishment: effects of drug taking history

Abstract: Rationale Abstinence from drug occurs in human addicts for several reasons, including the avoidance of adverse consequences.

A role for mesencephalic dopamine in activation: commentary on Berridge (2006)

Abstract: Ideas about the functions of the central dopamine (DA) system may seem to have evolved quite considerably in the last decade. While the theoretical debate based on classic neuropsychopharmacological approaches has become much more sophisticated and refined, perhaps the major new concepts have derived from (1) electrophysiological observations that fast phasic firing of cells in the ventral tegmental area appear to model an error prediction signal relevant to Pavlovian or temporal difference learning models (Schultz 2002), and from (2) the relative contributions of such phasic responses with the tonic mode of action of the same DA systems (Goto and Grace 2005). Both of these empirical advances were also matched by theoretical refinement; for example, in the domain of human cognitive neuroscience, the study of the role of DA in reinforcement learning and “error prediction” learning has become highly fashionable (see, e.g., Montague et al. 2004; Frank and O’Reilly 2006) and the tonic–phasic distinction has been a major new construct for modeling psychopathology, including genomic approaches (Bilder et al. 2004). One of the main thrusts of Berridge’s article is a critical analysis of the role of DA in reinforcement learning, and we particularly appreciate his attempt to differentiate his account from a learning standpoint, for example, by his experiments with serial conditioned stimuli (CSs). We are graciously assigned one of the competing perspectives to Berridge’s “incentive sensitization” hypothesis in terms of our speculations about the role of DA in habit learning. However, our position is a much more general one that in many ways is in harmony with that of Berridge, although on the basis of very different evidence. His discussion of a “motivational” role for the ascending DA system reminds us in many ways of notions that we have entertained in several previous articles (Robbins and Everitt 1982, 1987, 1992, 1995; Robbins et al. 1989). Thus, we suggested that functions of the central DA systems could be explained in terms of an “energetic” construct (i.e., one that accounts for the vigor and frequency of behavioral output) of “activation.” This activational state, which is particularly important in the modulation of behavioral (and cognitive) output, has to be distinguished from concepts of arousal that affect the efficiency of cortical processing. As posited in our 1992 review of the considerable empirical data already then available, activation (sometimes confusingly called “behavioral arousal”) is induced by many related states or stimuli, including food deprivation, “stress,” psychomotor stimulant drugs, aversive stimuli such as tail-pinch and foot-shock, novelty, CSs, including predictors of appetitive events such as food, and also of aversive events (Robbins and Everitt 1992). The range of these stimuli and states, incidentally goes far beyond the hypothesis that the midbrain DA system responds simply to error prediction signals, especially as the class of activating stimuli also includes novel stimuli under certain conditions (c.f. Bardo et al. 1990). However, we acknowledge that there is controversy about the relative sensitivity of the midbrain DA neurons to different states and stimuli—often arising from differences in the methods for indexing such changes, for example, electrophysiological, which are more sensitive to phasic Psychopharmacology (2007) 191:433–437 DOI 10.1007/s00213-006-0528-7

3,4-Methylenedioxymethamphetamine (MDMA) neurotoxicity in rats: a reappraisal of past and present findings

Abstract: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely abused illicit drug. In animals, high-dose administration of MDMA produces deficits in serotonin (5-HT) neurons (e.g., depletion of forebrain 5-HT) that have been interpreted as neurotoxicity. Whether such 5-HT deficits reflect neuronal damage is a matter of ongoing debate. The present paper reviews four specific issues related to the hypothesis of MDMA neurotoxicity in rats: (1) the effects of MDMA on monoamine neurons, (2) the use of “interspecies scaling” to adjust MDMA doses across species, (3) the effects of MDMA on established markers of neuronal damage, and (4) functional impairments associated with MDMA-induced 5-HT depletions. MDMA is a substrate for monoamine transporters, and stimulated release of 5-HT, NE, and DA mediates effects of the drug. MDMA produces neurochemical, endocrine, and behavioral actions in rats and humans at equivalent doses (e.g., 1–2 mg/kg), suggesting that there is no reason to adjust doses between these species. Typical doses of MDMA causing long-term 5-HT depletions in rats (e.g., 10–20 mg/kg) do not reliably increase markers of neurotoxic damage such as cell death, silver staining, or reactive gliosis. MDMA-induced 5-HT depletions are accompanied by a number of functional consequences including reductions in evoked 5-HT release and changes in hormone secretion. Perhaps more importantly, administration of MDMA to rats induces persistent anxiety-like behaviors in the absence of measurable 5-HT deficits. MDMA-induced 5-HT depletions are not necessarily synonymous with neurotoxic damage. However, doses of MDMA which do not cause long-term 5-HT depletions can have protracted effects on behavior, suggesting even moderate doses of the drug may pose risks.

Calculating utility: preclinical evidence for cost–benefit analysis by mesolimbic dopamine

Abstract: Rationale Throughout our lives we constantly assess the costs and benefits of the possible future outcomes of our actions and use this information to guide behavior. There is accumulating evidence that dopamine contributes to a fundamental component of this computation—how rewards are compared with the costs incurred when obtaining them. Objective We review the evidence for dopamine’s role in cost–benefit decision making and outline a simple mathematical framework in which to represent the interactions between rewards, costs, behavioral state and dopamine. Conclusions Dopamine’s effects on cost–benefit decision making can be modeled using simple utility–function curves. This approach provides a useful framework for modeling existing data and generating experimental hypotheses that can be objectively and quantitatively tested by observing choice behavior without the necessity to account for subjective psychological states such as pleasure or desire. We suggest that dopamine plays a key role in overcoming response costs and enabling high-effort behaviors. A particularly important anatomical site of this action is the core of the nucleus accumbens. Here, dopamine is able to modulate activity originating from the frontal cortical systems that also assess costs and rewards. Internal deprivation states (e.g., hunger and thirst) also help to energize goal-seeking behaviors, probably in part by their rich influence on dopamine, which can in turn modify decision making policies.

Opioids for hedonic experience and dopamine to get ready for it.

Abstract: Background and rationale More than two decades ago, Wise proposed his “anhedonia hypothesis” to explain the role of dopamine in motivated behaviors. The hypothesis posits that dopamine mediates the pleasure experienced by reward obtainment. However, some experimental findings have contested this hypothesis and several authors have proposed alternative functions for dopamine with regard to motivation. Brain dopamine has been suggested to rather code for the preparatory aspects of behavior, while brain opioids seem to mediate the perception of the hedonic properties of rewards.

Involvement of dopamine D1 and D2 receptors in the nucleus accumbens core and shell in inhibitory response control.

Abstract: Rationale Impaired inhibitory control over behavior is a key feature in various psychiatric disorders, and recent studies indicated an important role for dopamine D1 and D2 receptors and the nucleus accumbens (Acb) in this respect.

Stress-induced relapse to cocaine seeking: roles for the CRF(2) receptor and CRF-binding protein in the ventral tegmental area of the rat.

Abstract: Footshock reinstates cocaine seeking in cocaine-experienced rats by inducing corticotropin-releasing factor (CRF) and glutamate release in the ventral tegmental area (VTA) and thus activating VTA dopaminergic neurons. Footshock-induced VTA glutamate release, dopamine activation and reinstatements are blocked by VTA administration of a α-helical CRF, a nonselective CRF receptor antagonist. The effects of selective CRF antagonists have not yet been reported. The present studies were designed to explore the roles of VTA CRF receptor subtypes and CRF-BP in these effects induced by footshock. Rats were first trained to lever-press for intravenous cocaine (1 mg/infusion/0.13 ml, FR-1 schedule), and then tested under extinction conditions until response rates returned to the pretraining baseline. Reinstatements, VTA glutamate and dopamine levels [microdialysis with high performance liquid chromatography (HPLC)] were then assessed, under various pharmacological conditions, after mild inescapable footshock. Footshock-induced reinstatement of cocaine seeking and release of VTA glutamate and dopamine were blocked by selective blockade of VTA CRF2 receptors (CRF2Rs) but not CRF1Rs. VTA perfusion of CRF or CRF2R agonists that have strong affinity for CRF-BP mimicked the effects induced by footshock while CRFR agonists that do not bind CRF-BP were ineffective. CRF6–33, which competes for the CRF binding site on CRF-BP, attenuated the effects of CRF or urocortin I on VTA glutamate and dopamine release and on reinstatement of cocaine seeking. The present studies revealed a role of VTA CRF-BP and suggest an involvement of CRF2R in the effectiveness of stress in triggering glutamate and dopamine release and cocaine seeking in drug-experienced animals.

Opposing effects of 5-HT(2A) and 5-HT(2C) receptor antagonists in the rat and mouse on premature responding in the five-choice serial reaction time test.

Abstract: Serotonin (5-HT) has been linked to impulsivity with recent data suggesting that different receptor sub-types exert opposing influences on this behaviour. This work characterised the effects of 5-HT2A (ketanserin, (±)2,3-dimethoxyphenyl-1-[2–4-(piperidine)-methanol] [M100907]), 5-HT2B (6-chloro-5-methyl-1-(5-quinolylcarbamoyl) indoline [SB215505]) and 5-HT2C (6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbomyl] indoline [SB242084]) receptor antagonists on impulsive behaviour, measured in the five-choice serial reaction time test (5CSRTT), in rats and mice. The effects of (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 (Ro60-0175), two compounds that have been used extensively as agonists for the 5-HT2A and 5-HT2C receptor, were also measured. Rats and mice were trained on the 5CSRTT in which reinforcement is earned for detecting and correctly responding to brief presentations of a stimulus light. Impulsivity in this task is measured as premature responding, before stimulus presentation. Several variants of the task were used in which the inter-trial interval (ITI) length was manipulated to alter basal levels of premature responding. In the rat, ketanserin and M100907 reduced and SB242084 enhanced premature responding. SB215505 had no effect. DOI generally disrupted responding, while Ro60-0175 reduced premature responding when a long ITI was used. In mice, M100907 reduced and SB242084 increased premature responding when the ITI was lengthened. The effects of these drugs on other aspects of performance were less robust. M100907 and ketanserin did not affect response accuracy but tended to slow speed of responding; SB242084 occasionally increased speed of responding and slightly reduced accuracy. Serotonin exerts both excitatory and inhibitory influences on motor impulsivity via 5-HT2A and 5-HT2C receptors in both rats and mice.

Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study.

Abstract: Rationale The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients.

Experimental manipulation of attentional biases in heavy drinkers: do the effects generalise?

Abstract: Rationale In heavy drinkers, training attention towards alcohol cues increases alcohol craving, but it is not clear if effects of ‘attentional training’ generalise to novel stimuli and measurement procedures.

The CRF1 receptor antagonist antalarmin attenuates yohimbine-induced increases in operant alcohol self-administration and reinstatement of alcohol seeking in rats

Abstract: Yohimbine is an alpha-2 adrenoreceptor antagonist that provokes stress- and anxiety-like responses in both humans and laboratory animals. In rats, yohimbine increases operant alcohol self-administration and reinstates alcohol seeking. In this study, we assess whether these effects of yohimbine are attenuated by systemic injections of the corticotrotropin-releasing factor 1 (CRF1) receptor antagonist antalarmin. In Exp. 1, we trained rats to lever press for alcohol solutions (12% w/v, 1 h/day) over several weeks; during training, the response requirement was increased from a fixed-ratio-1 (FR-1) to a fixed-ratio-3 (FR-3) reinforcement schedule. We then tested the effect of antalarmin (10 or 20 mg/kg) on yohimbine (1.25 mg/kg)-induced increases in operant alcohol self-administration (FR-3 reinforcement schedule). Subsequently, we assessed the effect of antalarmin on yohimbine-induced increases in plasma corticosterone levels in the previously self-administering rats. In Exp. 2, we trained the rats to self-administer alcohol as in Exp. 1, and after extinction of the alcohol-reinforced lever responding over 13 days, we tested antalarmin’s effect on yohimbine-induced reinstatement of alcohol seeking. Yohimbine increased operant alcohol self-administration and reinstated alcohol seeking after extinction. These effects of yohimbine were attenuated by antalarmin. Antalarmin injections in the absence of yohimbine had no effect on either operant alcohol self-administration or extinction responding. Antalarmin had no effect on yohimbine-induced corticosterone release in alcohol-experienced rats. These results suggest that extrahypothalamic CRF1 receptors are involved in the effect of yohimbine on operant alcohol self-administration and on relapse to alcohol seeking and support the notion that CRF1 receptor antagonists should be considered in alcohol addiction treatment.

Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality.

Abstract: Rationale Manipulations of the endocannabinoid/fatty acid amide hydrolase (FAAH) signaling systems result in conflicting and paradoxical effects in rodent models of emotional reactivity.

Differential effects of modafinil and methylphenidate on stop-signal reaction time task performance in the rat, and interactions with the dopamine receptor antagonist cis-flupenthixol.

Abstract: Rationale The stop-signal reaction time (SSRT) task measures inhibition of a response that has already been initiated, i.e. the ability to stop. ‘Impulsive’ human subjects, e.g. with attention deficit and hyperactivity disorder (ADHD), have longer SSRTs. Both SSRT and go-trial reaction time (GoRT) may be sensitive to drugs such as d-amphetamine, methylphenidate and modafinil, both in normal subjects and those with ADHD.

Delay discounting predicts cigarette smoking in a laboratory model of abstinence reinforcement

Abstract: Rationale Higher rates of delay discounting, or impulsive choice, may be related to relapse during abstinence reinforcement interventions for cigarette smoking, and a transdermal nicotine patch may attenuate delay discounting.

Heterozygous neuregulin 1 mice are more sensitive to the behavioural effects of Δ9-tetrahydrocannabinol

Abstract: Rationale Cannabis use may precipitate schizophrenia especially if the individual has a genetic vulnerability to this mental disorder. Human and animal research indicates that neuregulin 1 (Nrg1) is a susceptibility gene for schizophrenia.

Alcohol cues increase cognitive impulsivity in individuals with alcoholism.

Abstract: Individuals with alcoholism are characterized by both attentional bias for alcohol cues and prepotent response inhibition deficit. We tested the hypothesis that alcoholics exhibit greater cognitive disinhibition when the response to be suppressed is associated with alcohol-related information. Forty recently detoxified individuals with alcoholism were compared with 40 healthy non-substance abusers on the “Alcohol-Shifting Task”, a variant of the go/no-go paradigm requiring a motor response to targets and no response to distracters. The aim was to test the ability of alcoholics to discriminate between alcohol-related and neutral words. Sometimes, the alcohol-related words were the targets for the “go” response, with neutral words as distracters, sometimes the reverse. Several shifts in target type occurred during the task. Alcoholics made significantly more commission errors (i.e., press a key when a distracter displayed) and more omission errors (i.e., not press a key when a target displayed) than controls. Moreover, the number of commission errors was greater in alcoholics when alcohol-related stimuli had to be detected. These results demonstrate that alcoholics exhibit a basic prepotent response inhibition deficit, which is enhanced when the response to be suppressed is related to alcohol. We discuss clinical and theoretical implications of these findings.

Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test.

Abstract: Rationale Few studies have investiga.ted whether the behavioral effects elicited by different types of antidepressant drugs are mediated by either serotonin (5-HT) or the catecholamines norepinephrine (NE) and dopamine (DA).

In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders

Abstract: Data from both preclinical and clinical studies have provided proof of concept that modulation of limbic and forebrain glutamate, via mGlu2/3 receptor agonists, might provide therapeutic benefits in many psychiatric disorders including schizophrenia and anxiety. The aim of this study was to assess the efficacy of a structurally novel, potent, selective mGlu2/3 receptor agonist with improved bioavailability (LY404039) in animal models predictive of antipsychotic and anxiolytic efficacy. LY404039 was assessed in amphetamine- and phencyclidine-induced hyperlocomotion, conditioned avoidance responding, fear-potentiated startle, marble burying, and rotarod behavioral tests. Monoamine release and turnover were assessed using microdialysis and ex vivo tissue levels. LY404039 attenuated amphetamine- and phencyclidine-induced hyperlocomotion (3–30 and 10 mg/kg, respectively). LY404039 (3–10 mg/kg) inhibited conditioned avoidance responding. LY404039 also reduced fear-potentiated startle in rats (3–30 μg/kg) and marble burying in mice (3–10 mg/kg), indicating anxiolytic-like effects. Importantly, LY404039 did not produce sedative effects or motor impairment as measured by rotarod performance and lack of escape failures in the conditioned avoidance task (at doses up to 30 and 10 mg/kg, respectively). LY404039 (10 mg/kg) also increased dopamine and serotonin release/turnover in the prefrontal cortex. These results demonstrate the broad preclinical efficacy of LY404039 across multiple animal models of antipsychotic and anxiolytic efficacy. Additionally, this compound modulates mesocortical neurotransmission and provides a novel mechanism for the treatment of psychiatric disorders that may be associated with improved efficacy and reduced incidence of undesirable side effects. As glutamatergic dysfunction has been linked to the etiology of schizophrenia, clinical studies with more potent mGlu2/3 agonists, such as LY404039, may be useful to explore the validity of this hypothesis.

Efficacy and safety of atomoxetine for attention-deficit/hyperactivity disorder in children and adolescents-meta-analysis and meta-regression analysis.

Abstract: The objective of this study was to evaluate the efficacy and safety of atomoxetine in children and adolescents. We searched for studies published between 1985 and 2006 through Medline, PubMed, PsychInfo and Cochrane Central Register of Controlled Trials (CENTRAL 2006 Issue 3) using keywords related to atomoxetine and attention-deficit/hyperactivity disorder (ADHD) and scanned though reference lists. We included nine randomized placebo-controlled trials (atomoxetine:placebo = 1,150:678). Atomoxetine was superior (p < 0.01) to placebo in reducing ADHD symptoms across different scales (Attention-Deficit/Hyperactivity Disorder Rating Scale-IV, Conners’ Parent and Teacher Rating Scales-Revised:Short Form, Clinical Global Impression-Severity) rated by different raters (parent, teacher, clinician). The number-needed-to-treat (NNTs) for treatment response and relapse prevention were 3.43 (95% CI, 2.79–4.45) and 10.30 (95% CI, 5.89–40.62), respectively. High baseline ADHD symptoms (p = 0.02) was associated with greater reduction in ADHD symptoms, whereas male gender (p = 0.02), comorbid oppositional defiant disorder (ODD) status (p = 0.01) and ADHD hyperactive/impulsive subtype (p = 0.01) were associated with smaller reductions. The commonest adverse events were gastrointestinal [appetite decrease, number-needed-to-harm (NNH) = 8.81; abdominal pain, NNH = 22.48; vomiting, NNH = 29.96; dyspepsia, NNH = 49.38] and sleep related (somnolence, NNH = 19.41). Young age (p = 0.03) and high baseline hyperactive/impulsive symptoms (p < 0.01) were associated with more adverse events, whereas ADHD inattentive subtype (p = 0.04) was associated with less adverse events. Quality of life using Child Health Questionnaire (CHQ) improved (p < 0.01) with atomoxetine treatment. Both ADHD and ODD symptoms (p < 0.01) were reduced in comorbid ADHD+ODD, and ODD status was not associated with more adverse events. Efficacy and side effects were not altered by comorbid general anxiety disorder or major depression. Atomoxetine is efficacious in reducing ADHD symptoms. It may have a role in treating comorbid ODD or depression, and probably in comorbid anxiety.

Involvement of AMPA/kainate, NMDA, and mGlu5 receptors in the nucleus accumbens core in cue-induced reinstatement of cocaine seeking in rats.

Abstract: Rationale Nucleus accumbens glutamate transmission has been implicated in drug-seeking behavior, but the involvement of glutamate receptor subtypes in drug seeking maintained by drug-associated cues has not been fully investigated.