NEURAL Mechanisms of Drug Seeking Behavior

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Cocaine dependence is viewed as a chronic condition because of the high incidence of relapse that occurs even after prolonged periods of abstinence. Thus, successful treatment of cocaine dependence must include prevention of relapse. Factors contributing to relapse include incentive motivational effects (e.g., craving) produced by cocaine itself or by exposure to cocaine-associated cues (e.g., paraphernalia, cocaine-taking environment, etc). Recent evidence suggests that different neural mechanisms underlie incentive motivational effects of cocaine versus cocaine cues. Leading theories suggest that these mechanisms likely involve changes in monoamine systems, yet little research has been done to test this hypothesis in regard to the involvement of the monoamine, serotonin (5-HT). The objective of this proposal is to examine the role of 5-HT systems in incentive motivation for cocaine. The hypotheses are that increasing 5-HT brain levels or 5-HT1A stimulation will decrease incentive motivation for cocaine, whereas decreasing stimulation of 5-HT2 receptors will decrease incentive motivation for cocaine. These hypotheses will be tested by examining cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement that is thought to reflect motivation for cocaine) after administration of drugs that either alter serotonin release or stimulation of 5-HT1A or 5-HT2 receptors. The effects of these drugs on extinction of cocaine-seeking behavior and reinstatement by presentations of cocaine-paired cues will be examined in animals in a drug-free state. Next, effects of these drugs with and without cocaine co-administration on reinstatement of cocaine-seeking behavior will be examined. Finally, behavioral specificity of observed effects will be examined by comparing them to the effects of the drugs on sucrose-seeking behavior. These experiments will help to elucidate 5-HT mechanisms involved in incentive motivation for cocaine and will likely have important implications for developing treatments for cocaine dependence.