High rates of relapse to drug use after prolonged drug-free periods characterize the behavior of experienced heroin and cocaine users. The behavioral and neurochemical events that contribute to these high rates, however, are not well understood. Relapse can be induced in human subjects and laboratory animals by reexposure to the drug previously used, reexposure to environmental cues paired with drug self-administration, and by exposure to environmental stressors. We are using an animal model of relapse, a reinstatement model, to study brain systems and neurotransmitters involved in relapse induced by environmental stressors, conditioned drug cues and drug reexposure in heroin- and cocaine-experienced rats after prolonged drug-free periods. During the last year, we studied the molecular mechanisms underlying the time-dependent changes in responsiveness to cocaine-associated cues after withdrawal from the drug. The main finding of this line of research is the identification of long-lasting alterations following withdrawal from cocaine in brain-derived growth factor (BDNF) in the brain that may mediate the time-dependent changes in responsiveness to cocaine cues. In other studies we have found that the context of the drug environment is a potent stimulus for relapse to heroin seeking after withdrawal and we currently study the role of the glutamate system in the brain in this effect. We also have found that the drug yohimbine, which induces anxiety-like responses in humans, reliably reinstates methamphetamine-seeking behavior in rats after prolonged withdrawal periods of up to 7 weeks.
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