The increased need to treat illicit users of cocaine, and other psychomotor stimulants, requires understanding the neural substrates of its effects that are associated with drug withdrawal and residual craving that could lead to relapse. The results of conditioning experiments with animal models and human drug users have suggested that environmental stimuli associated with the injection of stimulants may come to elicit similar responses as the drug itself. these conditioned environmental stimuli associated with drug administration may contribute to drug craving and eventual relapse by producing physiological and neurochemical changes during a critical period following drug withdrawal. Examples of such stimuli in human addicts include drug-taking paraphernalia or the sight of a bar of place associated with taking drugs. The technique of in vivo microdialysis, which allows the direct measurement of neurotransmitter release, provides a method to examine the neural substrates that underlie conditioned drug effects. When these experiments are carried out in awake freely-moving animals, behavioral evidence for conditioned drug effects can be examined simultaneously with associated neurochemical changes. Although the pharmacology of cocaine has been studied extensively, little is known about the neural substrates underlying the conditioned effects of cocaine, which may provide important targets for understanding drug relapse or for designing potential pharmacotherapies that may treat drug relapse. The technique of in vivo microdialysis will be used to examine the release of dopamine, norepinephrine and serotonin in the nucleus accumbens, the brain region most implicated in the reinforcing effects of cocaine and amphetamine, in three different series of behavioral conditioning studies thought to be mediated by the nucleus accumbens. Repeated administration of cocaine or amphetamine sensitizes rats to their effects on subsequent injections provided that the environment cues associated with drug administration remain constant. The first series of studies will examine the influence of testing environment on the development of sensitization to the neurochemical and behavioral effects of cocaine and amphetamine following their repeated administration. The second series of studies will examine neurotransmitter release following the training and during the expression of conditioned place preference. Conditioned place preference provides a behavior thought to be associated with the rewarding effects of drugs where rats choose to remain n an environment that has previously been associated with injections of cocaine or amphetamine. The third series of studies will examine neurotransmitter release during responding for the presentation of secondary reinforcers that have been associated with the self-administration of cocaine or amphetamine. The presentation of secondary reinforcers, such as brief visual stimulus, associated with injections of cocaine or amphetamine can maintain lever pressing behavior even after the primary reinforcing effects of drug injections have been extinguished. These studies taken together will provide important new information concerning whether conditioned drug effects in rats and their neural substrates in the nucleus accumbens are sufficiently robust and persistent to provide a model for residual drug craving in drug addicts. Conditioned drug effects and their neurochemical substrates may then be considered targets for pharmacological intervention as residual effects of drug addiction that contribute to relapse during therapy.
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