Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia, and other neuropsychiatric disorders. Over the past three decades, the clinical definition of anhedonia has remained relatively unchanged, although cognitive psychology and behavioral neuroscience have expanded our understanding of other reward-related processes. Here, we review the neural bases of the construct of anhedonia that reflects deficits in hedonic capacity, and is also closely linked to the constructs of reward valuation, decision-making, anticipation, and motivation. The neural circuits subserving these reward-related processes include the ventral striatum, prefrontal cortical regions, and afferent and efferent projections. Understanding anhedonia and other reward-related constructs will facilitate diagnosis and treatment of disorders that include reward deficits as key symptoms.

In these experiments we sought to establish the intravenous (i.v.) self-administration of cocaine under a second-order schedule of reinforcement in order: (i) to obtain reliable, drug-free levels of responding with cocaine as a reinforcer, and (ii) to enable investigation of the neural mechanisms by which arbitrary cues gain motivational salience and, as conditioned reinforcers, control over drug-seeking behaviour. Initially, each infusion of cocaine was made contingent upon a response on one of two identical levers and was paired with a 20-s light conditioned stimulus (CS). Responses on the second lever were recorded, but had no programmed consequence. When rats acquired stable rates of self-administration, a second-order schedule of the type FRx(FRy:S) was introduced, with values of "x" being increased progressively to 10 and then "y" from 2 through 8. Priming (i.e. non-contingent) infusions of cocaine were never given. Once the first infusion was obtained under the second-order schedule, further infusions were made contingent on each response (to a maximum of ten infusions/day). Each stage was repeated daily until the first infusion of each session was achieved within a 5-min criterion. Rats with bilateral, excitotoxic lesions of the basolateral amygdala readily acquired the i.v. self-administration of cocaine under a continuous reinforcement schedule, initially administering more infusions and maintaining a slightly elevated level of self-administration than controls. Despite increased numbers of CS/drug pairings, basolateral amygdala-lesioned rats were severely impaired in the acquisition of the second-order schedule of i.v. cocaine reinforcement. Lesioned rats showed a cocaine dose-response function that was shifted upwards relative to control subjects. There was no significant difference between drug-naive amygdala-lesioned and control animals in the locomotor response to intraperitoneal injections of cocaine. These experiments indicate the feasibility and utility of second-order schedules in studying the neurobehavioural basis of cocaine-seeking behaviour. They suggest a dissociation in the neural mechanisms underlying cocaine-taking and cocaine seeking behaviour, and demonstrate the potential importance of the basolateral amygdala in the processes by which previously neutral stimuli gain control over drug-seeking behaviour.

Abstinence (CNS) hyperexcitability that can result, in varying degrees of severity, in profound physiological disturbances such as tremors, hyperthermia, seizures, rigidity, hyperreflexia, and hallucinations and delirium (1-3). This constellation of withdrawal signs is largely unique to the sedative-hypnotics, and withdrawal from this class of drugs can be life-threatening. Other classes of drugs, such as opiates and psychostimulants, are associated with different withdrawal syndromes. The opiate withdrawal syndrome, which has been described as an intense "flu-like state," includes symptoms such as lacrimation, rhinorrhea, sweating, dilated pupils, gooseflesh, intestinal spasm, diarrhea, hyperthermia, anorexia/weight loss, and muscle spasms (2, 4). Withdrawal from chronic abuse of psychostimulants such as cocaine and amphetamines is associated with relatively minor somatic disturbances, including fatigue and suppressed heart rate, and is primarily characterized by more affective or emotional signs such as depression, dysphoria, and anxiety (2, 5). These differences in withdrawal symptomatology are not unexpected given the vastly different pharmacodynamic mechanisms of action of sedative/hypnotic, opiate, and psychomotor stimulant drugs and the unique neuroanatomical localization of receptors with which theseThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. different drugs interact. However, there is some clinical evidence that chronic dependence and withdrawal from all three of these classes of abused drugs may share common symptomatology in the form of affective or emotional disturbances, such as irritability, restlessness, anxiety, and mood disturbances such as dysphoria, depression, and anhedonia (1, 2, 4-12). It has been shown in studies with rodents that ethanol, opiate, and psychostimulant withdrawal appear to produce a similar anxiety-like state (13).Furthermore, despite their distinct pharmacodynamic profiles, ethanol, opiates, and psychostimulants all share reinforcing or rewarding properties upon acute administration, which appear to involve activation of common reward circuits in the brain, including most notably the nucleus accumbens in the basal forebrain and its afferent connections from ventral midbrain (i.e., the ventral tegmental area) and limbic portions of the CNS (14-16).The symptoms of drug dependence have long been considered from the perspective of neuroadaptation theories. One such theory postulates that all positive reinforcers, including drugs of abuse, produce positive affective responses in the CNS that are opposed by negative affective responses as a natural consequence of an organism's propensity to maintain affective homeostasis (17-19). These negative affective consequences, which are hypothesized to be the consequence of neuroadaptations within the brain reward circuitry (17, 18), may upon termination of drug ad...

Nicotine is a major component of tobacco smoke contributing to the initiation and persistence of the harmful tobacco habit in human smokers. The reinforcing effects of nicotine likely arise through its ability to stimulate brain circuitry mediating the detection and experiencing of natural rewards. Nevertheless, remarkably little is known concerning the acute or long-lasting actions of nicotine on brain reward systems in vivo. Here, we investigated the effects of intravenously self-administered nicotine (0.03 mg/kg/infusion, free base) on the sensitivity of brain reward systems, reflected in alterations of intracranial self-stimulation (ICSS) thresholds in rats. Rats selfadministered nicotine during 1 or 12 h daily sessions, with reward thresholds assessed 1 h before and 15 min after each self-administration session. Control rats remained nicotine naïve throughout. Nicotine self-administration increased the sensitivity of brain reward systems, detected by post-nicotine lowering of reward thresholds in 1 and 12 h rats. This nicotine-enhanced sensitivity of reward systems was reversed by the high-affinity nicotinic receptor antagonist dihydro-b-erythroidine (DHbE; 3 mg/kg). Surprisingly, nicotine-induced excitation of reward systems persisted for at least 36 days after nicotine self-administration had ceased. Overall, these data demonstrate that rats can voluntarily consume quantities of nicotine sufficient to increase the sensitivity of brain reward systems, an action likely crucial in establishing and maintaining the nicotine habit. Moreover, self-administered nicotine resets the sensitivity of reward systems to a new increased level, thereby imprinting an indelible 'memory' of its effects in reward systems, an action that so far appears unique to nicotine among drugs of abuse.

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