Drug craving, the desire to experience the effect(s) of a previously experienced psychoactive substance, has been hypothesized to contribute significantly to continued drug use and relapse after a period of abstinence in humans. In more theoretical terms, drug craving can be conceptualized within the framework of incentive motivational theories of behavior and be defined as the incentive motivation to self-administer a psychoactive substance. The incentive-motivational value of drugs is hypothesized to be determined by a continuous interaction between the hedonic rewarding properties of drugs (incentive) and the motivational state of the organism (organismic state). In drug-dependent individuals, the incentive-motivational value of drugs (i.e., drug craving) is greater compared to non-drug-dependent individuals due to the motivational state (i.e., withdrawal) developed with repeated drug administration. In this conceptual framework, animal models of drug craving would reflect two aspects of the incentive motivation to self-administer a psychoactive substance. One aspect would be the unconditioned incentive (reinforcing) value of the drug itself. The other aspect would be relatively independent of the direct (unconditioned) incentive value of the drug itself and could be reflected in the ability of previously neutral stimuli to acquire conditioned incentive properties that could elicit drug-seeking and drug-taking behavior. Animal models of drug craving that permit the investigation of the behavioral and neurobiological components of these two aspects of drug craving are reviewed and evaluated. The models reviewed are the progressive ratio, choice, extinction, conditioned reinforcement and second-order schedule paradigms. These animal models are evaluated according to two criteria that are established herein as necessary and sufficient criteria for the evaluation of animal models of human psychopathology: reliability and predictive validity. The development of animal models of drug craving will have heuristic value and allow a systematic investigation of the neurobiological mechanisms of craving.

Basal forebrain dopamine (DA) and 5-HT neurotransmission has been implicated in the mediation of the acute reinforcing actions of ethanol. Neuroadaptation theories predict that compensatory changes in neurochemical systems that are activated by alcohol acutely may underlie symptoms of withdrawal after chronic administration. To test this hypothesis, the release of DA and 5-HT was monitored by microdialysis in the nucleus accumbens of dependent male Wistar rats at the end of a 3-5 week ethanol (8.7% w/v) liquid diet regimen, during 8 hr of withdrawal, and during renewed availability of ethanol involving (1) the opportunity to operantly self-administer ethanol (10% w/v) for 60 min, followed by (2) unlimited access to the ethanol-liquid diet. Results were compared to control groups pair-fed with ethanol-free liquid diet and trained to self-administer either ethanol or water. In nondependent rats, operant ethanol self-administration increased both DA and 5-HT release in the NAC. Withdrawal from the chronic ethanol diet produced a progressive suppression in the release of these transmitters over the 8 hr withdrawal period. Self-administration of ethanol reinstated and maintained DA release at prewithdrawal levels but failed to completely restore 5-HT efflux. 5-HT levels recovered rapidly, however, within 1 hr of reexposure to ethanol liquid diet. These findings suggest that deficits in accumbal monoamine release may contribute to the negative affective consequences ethanol withdrawal and, thereby, motivate ethanol-seeking behavior in dependent subjects.

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...

This study suggests that there is a window of modest analgesia for smoked cannabis, with lower doses decreasing pain and higher doses increasing pain.

Alcoholism is a complex behavioral disorder characterized by excessive consumption of ethanol, a narrowing of the behavioral repertoire toward excessive consumption, the development of tolerance and dependence, and impairment in social and occupational functioning. Animal models of the complete syndrome of alcoholism are difficult if not impossible to achieve, but validated animal models exist for many of the different components of the syndrome. Recent work has begun to define the neurocircuits responsible for the two major sources of reinforcement key to animal models of excessive ethanol intake: positive and negative reinforcement. Ethanol appears to interact with ethanol-sensitive elements within neuronal membranes that convey the specificity of neurochemical action. Ethanol reinforcement appears to be mediated by an activation of GABA-A receptors, release of opioid peptides, release of dopamine, inhibition of glutamate receptors, and interaction with serotonin systems. These neurocircuits may be altered by chronic ethanol administration as reflected by opposite effects during acute ethanol withdrawal and by the recruitment of other neurotransmitter systems such as the stress neuropeptide corticotropin-releasing factor. Future challenges will include a focus on understanding how these neuroadaptive changes convey vulnerability to relapse in animals with a history of ethanol dependence.