Reward Thresholds Research Articles

Neural processing of a cocaine-associated odor cue revealed by functional MRI in awake rats

Using an olfactory conditioning procedure, brain stimulation reward threshold measurements, and functional magnetic resonance imaging (fMRI), we investigated brain stimulation reward threshold change and fMRI neural activation in response to a cocaine-associated odor cue. In the first brain stimulation experiment, over 10 days of rate–frequency curve-shift testing, rats were administered intravenous cocaine (1.0mg/kg) paired with a contextual cue of peppermint odor previously placed in the operant chamber or they were given vehicle treatment (no cocaine) in the presence of no olfactory cue. Following a 14-day drug-free rest period, rats were again given the rate–frequency curve-shift threshold test with or without the odor cue. In a second experiment, rats were similarly conditioned with a peppermint odor but with intraperitoneally delivered cocaine (10mg/kg). After a 14 day rest period, rats were imaged on a 7-T MRI for their blood oxygen level dependent (BOLD) in response to the cocaine-paired peppermint odor versus an unpaired neutral lemon odor. In the brain stimulation experiment, expected significant reward threshold shifts were produced by cocaine and, importantly, about half that level of shift was produced by the paired contextual olfactory cue. In the fMRI experiment, the insular cortex showed a significantly greater BOLD activation in cocaine-treated versus saline-treated animals to the olfactory cue, but not with the unpaired lemon scent. These data are in agreement with previous studies suggesting a role of the insular cortex in attributing reward value (positive or negative) to conditioned odor stimuli.

Fibrillation atriale

An animal model can be viewed as an experimental paradigm developed for the purpose of studying a given phenomenon found in humans. Although there are no complete animal models of depression, anxiety, schizophrenia, or addiction, animal models do exist for many elements of the syndrome. Animal models for antidepressant medications include a number of tests with good predictive validity, but limited construct validity, and include the forced swim test, modified swim test, learned helplessness, olfactory bulbectomy, differential reinforcement of low rates of responding, maternal deprivation, neonatal clomipramine treatment, social stress in shrews, chronic mild stress, agonistic behavior, and Flinders sensitive rats. Animal models of depression that have face validity and construct validity for a key element of depression are reward deficits measured by brain stimulation reward and progressive-ratio responding for a natural reward. Widely used animal models of generalized anxiety include the operant conflict test, elevated plus maze, defensive withdrawal, defensive burying, and social interaction, all of which have face and predictive validity. Animal models for individual types of anxiety disorder remain a challenge, with some advances in posttraumatic stress disorder, which includes models of repeated shock stressors, repeated social stressors, and a single prolonged stress paradigm. Animal models of schizophrenia are limited by the limited knowledge of the pathophysiology of the disease but include pharmacological, developmental, and genetic models combined with behavioral tests with some face and contruct validity, such as locomotor activity (positive symptoms), prepulse inhibition of the startle response (attention), latent inhibition (attention), social withdrawal (negative symptoms), and measures of executive function. Animal models of addiction can be organized within the stages of the addiction cycle, including: binge/intoxication (drug or alcohol self-administration, conditioned place preference, brain stimulation reward thresholds), withdrawal/negative affect (anxiety-like responses, conditioned place aversion, elevated reward thresholds, withdrawal-induced increases in drug self-administration), and preoccupation/anticipation (drug-induced reinstatement, cue-induced reinstatement, stress-induced reinstatement). These models have excellent face and construct validity and have led to major insights into the neurobiological mechanisms of addiction. Animal models remain a key heuristic approach to elucidation of the pathophysiology and treatment of psychiatric disorders.

Predictors and correlates of taste preferences in European children: The IDEFICS study

The present study investigated taste preferences in a sample of 1705 children aged 6 to 9years from survey centres in Italy, Estonia, Cyprus, Belgium, Sweden, Germany, Hungary, and Spain and aimed to identify factors correlated with taste preference. Children’s preferences for varying levels of sucrose (sweet) in apple juice and fat, sodium chloride (salt) and monosodium glutamate (umami) in crackers were assessed using paired-comparison tests. Socio-demographics (age, sex, parental education), early feeding practises (breastfeeding, introduction of fruits), parenting behaviour (TV viewing, using food as a reward) and taste threshold sensitivity for sucrose (sweet), sodium chloride (salt), caffeine (bitter) and monosodium glutamate (umami) were investigated as possible correlates of taste preferences. Parents reported on socio-demographics, early feeding and parenting behaviour. Taste thresholds were determined via a paired-comparison staircase method. Country of residence was the strongest factor related to preferences for all four tastes. Taste preferences also differed by age. Preference for sugar and salt increased between 6 and 9years of age while preference for monosodium glutamate decreased. The age differences remained significant even after adjustment for sex, country of residence, parental education and early feeding habits. Sex, parental education, early feeding habits, TV viewing, using food as a reward and taste thresholds were not consistently related to taste preferences among the survey centres. In summary, the results highlight the importance of culture and age in taste preferences in children younger than 10years of age.

A dysphoric-like state during early withdrawal from extended access to methamphetamine self-administration in rats

Negative emotional states during drug withdrawal may contribute to compulsive drug intake and seeking in humans. Studies suggest that extended access to methamphetamine induces compulsive drug intake in rats. The present study tested the hypothesis that compulsive methamphetamine intake in rats with extended access is associated with negative emotional states during drug withdrawal. Rats with short (1h, ShA) and extended access (6h, LgA) to methamphetamine self-administration (0.05mg/kg/infusion) were tested for reward thresholds using intracranial self-stimulation (ICSS). Different groups of ShA and LgA rats were examined for depression-like and anxiety-like states in the novelty-suppressed feeding, open field, defensive burying, and forced swim tests. With extended access, ICSS thresholds gradually increased, which was correlated with the increase of drug intake. During drug withdrawal, the increased ICSS thresholds returned to levels observed before exposure to extended access to methamphetamine. Upon re-exposure to extended access to methamphetamine, ICSS thresholds showed a more rapid escalation than during the initial exposure. LgA rats showed a longer latency to approach chow in the center of a novel field and remained immobile longer in the forced swim test than ShA rats did during early withdrawal. In contrast, ShA rats actively buried an aversive shock probe whereas LgA rats remained immobile in the defensive burying test. The data suggest that extended access to methamphetamine produces a more depressive-like state than anxiety-like state in rats during early withdrawal.

The triple reuptake inhibitor DOV 216,303 induces long-lasting enhancement of brain reward activity as measured by intracranial self-stimulation in rats

Triple reuptake inhibitors (TRIs) are potential new antidepressants, which not only enhance brain serotonin and norepinephrine concentrations but also increase dopamine levels. Therefore TRIs are believed to have faster therapeutic onset than SSRIs, and may be particularly useful for the treatment of anhedonia (i.e. inability to experience pleasure), one of the core symptoms of major depression. The current study aimed at getting better insight into the rewarding properties of DOV 216,303, which is a TRI, regarding its possible use to treat anhedonia. It is known that psychostimulant drugs lower intracranial self-stimulation (ICSS) reward thresholds, reflecting enhanced brain reward activity, whereas withdrawal from those compounds mostly results in increased ICSS thresholds. Therefore we assessed the effects of DOV 216,303 on ICSS thresholds in rats. Animals were trained in the discrete-trial current-threshold procedure and after stable ICSS reward thresholds were established, animals received one injection per day of DOV 216,303 (20mg/kg) or amphetamine (5mg/kg) for four consecutive days. ICSS thresholds were assessed 3, 6, and 23h after each injection. DOV 216,303 decreased ICSS thresholds up to 6h after drug treatment. To our knowledge this is the first time that a triple reuptake inhibitor, DOV 216,303, induces relatively long-lasting enhancement of brain reward activity. Elevated ICSS thresholds were found after amphetamine administration, which is consistent with previously reported reward deficits induced after amphetamine-withdrawal.

Risk-Variant Policy Switching to Exceed Reward Thresholds

This paper presents a decision-theoretic planning approach for probabilistic environments where the agent's goal is to win, which we model as maximizing the probability of being above a given reward threshold. In competitive domains, second is as good as last, and it is often desirable to take risks if one is in danger of losing, even if the risk does not pay off very often. Our algorithm maximizes the probability of being above a particular reward threshold by dynamically switching between a suite of policies, each of which encodes a different level of risk. This method does not explicitly encode time or reward into the state space, and decides when to switch between policies during each execution step. We compare a risk-neutral policy to switching among different risk-sensitive policies, and show that our approach improves the agent's probability of winning.

Effects of the specific α4β2 nAChR antagonist, 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine, on nicotine reward-related behaviors in rats and mice.

Alleviating addiction to tobacco products could prevent millions of deaths. Investigating novel compounds selectively targeting α4β2 nAChRs hypothesized to have a key role in the rewarding effects of nicotine may be a useful approach for future treatment. The present study was designed to evaluate 2-fluoro-3-(4-nitrophenyl) deschloroepibatidine (4-nitro-PFEB), a potent competitive antagonist of neuronal α4β2 nAChRs, in several animal models related to nicotine reward: drug discrimination, intracranial self-stimulation (ICSS), conditioned place preference, and limited access to self-administration. Long Evans rats were trained in a two-lever discrimination procedure to discriminate 0.4 mg/kg nicotine (s.c.) from saline. Male Sprague-Dawley rats were stereotaxically implanted with electrodes and trained to respond for direct electrical stimulation of the medial forebrain bundle. ICR mice were evaluated using an unbiased place preference paradigm, and finally, male Wistar rats were implanted with intrajugular catheters and tested for nicotine self-administration under limited access (1 h/day). 4-Nitro-PFEB attenuated the discriminative stimulus effects of nicotine, but alone did not produce nicotine-like discriminative stimulus effects. Nicotine-induced facilitation of ICSS reward thresholds was reversed by 4-nitro-PFEB, which alone had no effect on thresholds. 4-Nitro-PFEB also blocked the conditioned place preference produced by nicotine, but alone had no effect on conditioned place preference. Finally, 4-nitro-PFEB dose-dependently decreased nicotine self-administration. These results support the hypothesis that neuronal α4β2 nAChRs play a key role in mediating the rewarding effects of nicotine and further suggest that targeting α4β2 nAChRs may yield a potential candidate for the treatment of nicotine dependence.

Investigation of the role of corticotropin‐releasing factor receptors within the central amygdala and basolateral amygdala during nicotine withdrawal in rats

Abrupt cessation of tobacco smoking in humans is associated with negative affective symptoms such as depressed mood and anxiety. Evidence indicates that this dysphoric state associated with nicotine withdrawal is one of the motivational factors for the continuation of tobacco smoking. Cessation of chronic nicotine administration in rodents induces affective withdrawal signs which can be investigated using the intracranial self‐stimulation (ICSS) procedure. The amygdala is hypothesized to play a key role in both the positive and negative reinforcing properties of drugs of abuse. Injections of the specific CRF1 antagonist R278995/CRA0450 into the central amygdala attenuated elevations in brain reward thresholds, whereas injections into the basolateral amygdala showed no effect. Funded by NIDA Grant # DA023575

Choosing ecosystem service investments that are robust to uncertainty across multiple parameters

Info-gap decision theory facilitates decision making for problems in which uncertainty is large and probability distributions of uncertain variables are unknown. The info-gap framework allows the decision maker to maximize robustness to failure in the presence of uncertainty, where uncertainty is in the parameters of the model and failure is defined as the model output falling below some minimally acceptable performance threshold. Info-gap theory has found particular application to problems in conservation biology and ecological economics. In this study, we applied info-gap theory to an ecosystem services tradeoff case study in which a decision maker aiming to maximize ecosystem service investment returns must choose between two alternative land uses: native vegetation conservation or the establishment of an exotic timber plantation. The uncertain variables are the carbon price and the water price. With a "no-information" uncertainty model that assumes equal relative uncertainty across both variables, info-gap theory identifies a minimally acceptable reward threshold above which conservation is preferred, but below which plantation establishment is preferred. However, with an uncertainty model that allows the carbon price to be substantially more uncertain than the water price, conservation of native vegetation becomes an economically more robust investment option than establishing alien pine plantations. We explored the sensitivity of the results to the use of alternative uncertainty models, including asymmetric uncertainty in individual variables. We emphasize the general finding that the results of info-gap analyses can be sensitive to the choice of uncertainty model and that, therefore, future applications to ecological problems should be careful to incorporate all available qualitative and quantitative information relating to uncertainties or should at least justify the no-information uncertainty model.

Adolescent exposure to methylphenidate has no effect on the aversive properties of cocaine in adulthood

Methylphenidate is the most widely prescribed pharmacotherapeutic treatment of AD/HD in children and teens and has actions that are also involved in drug reward and reinforcement. Its clinical use has often raised concerns over the possibility that it could potentiate the risk for later drug-related problems. Animals exposed to methylphenidate during adolescence exhibit attenuated cocaine-induced conditioned place preference, but tend to self-administer cocaine more quickly than controls. A drug's abuse potential, as reflected by self-administration, is thought to be the product of a balance between its rewarding and aversive properties, thus the present research assessed the effects of adolescent exposure to methylphenidate on conditioned taste aversions induced by cocaine in adulthood in 132 male Sprague Dawley rats. Although cocaine induced robust dose-dependent taste aversions in accordance with previous research, there were no effects of adolescent exposure to methylphenidate in spite of evidence that it was behaviorally active. The present results indicate that changes in adult cocaine self-administration are not likely mediated by changes in the aversive response. The possibility that such changes are a function of reductions in reward threshold is discussed.

Voluntary running-wheel exercise decreases the threshold for rewarding intracranial self-stimulation.

Physical exercise has mood-enhancing and antidepressant properties although the mechanisms underlying these effects are not known. The present experiment investigated the effects of prolonged access to a running wheel on electrical self-stimulation of the lateral hypothalamus (LHSS), a measure of hedonic state, in rats. Rats with continuous voluntary access to a running wheel for either 2 or 5 weeks exhibited dramatic leftward shifts in the effective current 50 (ECu50; current value that supports half of maximum responding) of their LHSS current-response functions compared to their baselines, indicating a decrease in reward threshold, whereas control rats current-response functions after 2 or 5 weeks were not significantly different from baseline. An inverse correlation existed between the change in ECu50 from baseline and the amount an animal had run in the day prior to LHSS testing, indicating that animals that exhibited higher levels of running showed a more robust decrease in LHSS threshold. We conclude that long-term voluntary exercise increases sensitivity to rewarding stimuli, which may contribute to its antidepressant properties.

Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats

The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA.

Lipopolysaccharide induces anhedonia-like reward deficits, reflected by long-term increases in brain stimulation reward thresholds

Lipopolysaccharide induces anhedonia-like reward deficits, reflected by long-term increases in brain stimulation reward thresholds

Withdrawal from chronic cocaine administration induces deficits in brain reward function in C57BL/6J mice

Anhedonia is a major symptom of cocaine withdrawal, whereas euphoria characterizes the effects of acute administration of this drug in humans. These mood states can be measured quantitatively in animals with brain reward thresholds obtained from the intracranial self-stimulation (ICSS) procedure. Studies have previously reported the reward-enhancing effects of acute cocaine administration using the ICSS procedure in mice, but the effects of chronic cocaine administration and withdrawal on brain reward thresholds have not been widely investigated in this species. Cocaine withdrawal was induced in C57BL/6J mice by removal of intraperitoneal osmotic minipumps that delivered cocaine (90 or 180 mg/kg/day, salt) for 72 h. Mice were tested in the ICSS procedure 3–100 h post-pump removal. Anxiety-like behavior was assessed in the light–dark box 24 h post-pump removal. After an 18-day washout period, tolerance and sensitization to the reward-enhancing effects of cocaine were assessed by injecting bolus cocaine intraperitoneally (0, 2.5, 5, and 10 mg/kg). The results indicated that 72 h administration of 90 and 180 mg/kg/day cocaine significantly lowered brain reward thresholds. Withdrawal from 90 and 180 mg/kg/day of cocaine administration elevated ICSS thresholds to similar extents. No anxiety-like behavior was observed in the light–dark box during withdrawal from chronic cocaine administration, although the number of transitions between compartments and locomotion in the dark compartment markedly decreased. Chronic cocaine administration did not induce tolerance or sensitization to the reward-enhancing effects of acute cocaine. In conclusion, alterations in mood states induced by cocaine administration and withdrawal in mice can be measured using the ICSS procedure.

Decreases in Brain Reward Function Reflect Nicotine- and Methamphetamine-Withdrawal Aversion in Rats

The purpose of the present study was to investigate whether brain reward function decreases during withdrawal from nicotine and methamphetamine, and whether decreased reward function is related to aversion during withdrawal from these drugs. For that purpose, male Sprague-Dawley rats were chronically infused subcutaneously with 9 mg/kg per day nicotine, or with 6 mg/kg per day methamphetamine using osmotic minipumps. In an intracranial self-stimulation (ICSS) paradigm, chronic infusion of nicotine and methamphetamine decreased the thresholds for lateral hypothalamic ICSS, whereas their antagonists, mecamylamine and haloperidol increased the ICSS thresholds in the rats treated with nicotine and methamphetamine, respectively. In a conditioned place aversion paradigm, mecamylamine and haloperidol produced place aversion in nicotine- and methamphetamine-infused rats, respectively. Interestingly, elevations in ICSS reward thresholds and place aversion during mecamylamine-precipitated nicotine withdrawal were almost the same in magnitude as those observed during haloperidol-precipitated methamphetamine withdrawal. The present study indicates that 1) brain reward function decreased during nicotine and methamphetamine withdrawal, and 2) a decrease in reward function may reflect the negative affective state (aversion) during withdrawal from nicotine and methamphetamine.

Effects of insulin and leptin in the ventral tegmental area and arcuate hypothalamic nucleus on food intake and brain reward function in female rats

There is evidence for a role of insulin and leptin in food intake, but the effects of these adiposity signals on the brain reward system are not well understood. Furthermore, the effects of insulin and leptin on food intake in females are underinvestigated. These studies investigated the role of insulin and leptin in the ventral tegmental area (VTA) and the arcuate hypothalamic nucleus (Arc) on food intake and brain reward function in female rats. The intracranial self-stimulation procedure was used to assess the effects of insulin and leptin on the reward system. Elevations in brain reward thresholds are indicative of a decrease in brain reward function. The bilateral administration of leptin into the VTA (15–500 ng/side) or Arc (15–150 ng/side) decreased food intake for 72 h. The infusion of leptin into the VTA or Arc resulted in weight loss during the first 48 (VTA) or 24 h (Arc) after the infusions. The administration of insulin (0.005–5 mU/side) into the VTA or Arc decreased food intake for 24 h but did not affect body weights. The bilateral administration of low, but not high, doses of leptin (15 ng/side) or insulin (0.005 mU/side) into the VTA elevated brain reward thresholds. Neither insulin nor leptin in the Arc affected brain reward thresholds. These studies suggest that a small increase in leptin or insulin levels in the VTA leads to a decrease in brain reward function. A relatively large increase in insulin or leptin levels in the VTA or Arc decreases food intake.

Neurobiology of Addiction

Neurobiology of Addiction

Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol addiction as a reward deficit disorder.

Alcoholism can be defined by a compulsion to seek and take drug, loss of control in limiting intake, and the emergence of a negative emotional state when access to the drug is prevented. Alcoholism impacts multiple motivational mechanisms and can be conceptualized as a disorder that includes a progression from impulsivity (positive reinforcement) to compulsivity (negative reinforcement). The compulsive drug seeking associated with alcoholism can be derived from multiple neuroadaptations, but the thesis argued here is that a key component involves the construct of negative reinforcement. Negative reinforcement is defined as drug taking that alleviates a negative emotional state. The negative emotional state that drives such negative reinforcement is hypothesized to derive from dysregulation of specific neurochemical elements involved in reward and stress within the basal forebrain structures involving the ventral striatum and extended amygdala, respectively. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission, such as decreased dopamine and γ-aminobutyric acid function in the ventral striatum, but also recruitment of brain stress systems, such as corticotropin-releasing factor (CRF), in the extended amygdala. Acute withdrawal from chronic alcohol, sufficient to produce dependence, increases reward thresholds, increases anxiety-like responses, decreases dopamine system function, and increases extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists also block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the compulsivity of alcoholism. Other components of brain stress systems in the extended amygdala that interact with CRF and that may contribute to the negative motivational state of withdrawal include norepinephrine, dynorphin, and neuropeptide Y. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for a negative emotional state that is responsible for the negative reinforcement driving, at least partially, the compulsivity of alcoholism.

ADHD and EEG-neurofeedback: a double-blind randomized placebo-controlled feasibility study

Electroencephalography (EEG)-neurofeedback has been shown to offer therapeutic benefits to patients with attention-deficit/hyperactivity disorder (ADHD) in several, mostly uncontrolled studies. This pilot study is designed to test the feasibility and safety of using a double-blind placebo feedback-controlled design and to explore the initial efficacy of individualized EEG-neurofeedback training in children with ADHD. Fourteen children (8–15 years) with ADHD defined according to the DSM-IV-TR criteria were randomly allocated to 30 sessions of EEG-neurofeedback (n = 8) or placebo feedback (n = 6). Safety measures (adverse events and sleep problems), ADHD symptoms and global improvement were monitored. With respect to feasibility, all children completed the study and attended all study visits and training sessions. No significant adverse effects or sleep problems were reported. Regarding the expectancy, 75% of children and their parent(s) in the active neurofeedback group and 50% of children and their parent(s) in the placebo feedback group thought they received placebo feedback training. Analyses revealed significant improvements of ADHD symptoms over time, but changes were similar for both groups. This pilot study shows that it is feasible to conduct a rigorous placebo-controlled trial to investigate the efficacy of neurofeedback training in children with ADHD. However, a double-blind design may not be feasible since using automatic adjusted reward thresholds may not work as effective as manually adjusted reward thresholds. Additionally, implementation of active learning strategies may be an important factor for the efficacy of EEG-neurofeedback training. Based on the results of this pilot study, changes are made in the design of the ongoing study.Electronic supplementary materialThe online version of this article (doi:10.1007/s00702-010-0524-2) contains supplementary material, which is available to authorized users.

The role of nucleus accumbens shell GABA receptors on ventral tegmental area intracranial self-stimulation and a potential role for the 5-HT2Creceptor

Brain γ-aminobutyric acid (GABA) and 5-hydroxytryptamine (5-HT)(2C) receptors are implicated in the neuronal regulation of reward- and aversion-related behaviour. Within the mesocorticolimbic pathways of the brain, relationships between GABA containing neurons and 5-HT(2C) receptor activity may be important in this context. The primary aim of this study was to investigate the role of NAc shell GABA receptors on ventral tegmental area intracranial self-stimulation (ICSS) and to examine the systemic effects of GABAergic ligands in this context. The second aim was to investigate the relationship between GABA receptor- and 5-HT(2C) receptor-related ICSS behaviour, using systemic administration of the selective agonist WAY 161503. Locomotor activity was assessed to compare the potential motor effects of drugs; feeding behaviour and intra-NAc injections of amphetamine (1.0 µg/side) were used as positive controls. When administered systemically the GABA(A) receptor agonist muscimol and antagonist picrotoxin did not selectively change ICSS reward thresholds, although the 5-HT(2C) receptor agonist WAY 161503 (1.0 mg/kg) decreased reward measures. Intra-NAc shell administration of muscimol (225 ng/side) and picrotoxin (125 ng/side), respectively, decreased and increased measures of reward. Intra-NAc shell baclofen (0-225 ng/side; GABA(B) receptor agonist) did not affect any ICSS measures although it increased feeding. Combining picrotoxin and WAY 161503 attenuated the effects of each. These results suggest that a 5-HT(2C) and GABA(A) receptor-mediated neuronal relationship in the NAc shell may be relevant for the regulation of brain reward pathways.