An elucidation of the neural mechanisms of action of cocaine is required if we are to identify pharmacological agents which might block or reverse its psychotropic and toxic effects. Much of this research has focused on the importance of dopamine (DA) mesolimbic circuits in mediating the behavioral effects of cocaine. However, cocaine also interferes with serotonin (5- hydroxytryptamine; 5-HT) function. As the mesolimbic DA system is heavily innervated by 5-HT neurons of the dorsal (DR) and median (MR) raphe, specific alterations in 5-HT control of DA mesolimbic systems may in part affect the consequences of acute and chronic cocaine. In fact, the etiology of psychiatric disorders (anxiety, depression and psychoses) experienced by cocaine abusers could include aberrations in 5-HT function. However, understanding the actions of cocaine is complicated by limited information regarding the sites and mechanisms by which 5-HT controls DA mesolimbic function. The goals of the present proposal are three-fold: (1) to assess the role of 5-HT in the behavioral effects of cocaine; (2) to study further the mechanism(s) by which acute and chronic cocaine interact with 5-HT raphe systems; and (3) to characterize 5-HT modulatory control of DA mesolimbic systems. We will test the hypothesis that 5-HT innervation of DA mesolimbic systems is important to the unconditioned and conditioned behavioral effects of cocaine. Drug discrimination procedures will provide a model of the subjective effects of cocaine in humans and will allow us to determine the importance of 5-HTergic mechanisms to a behavior which is highly correlated with the abuse potential of cocaine. Secondly, cocaine- induced locomotor hyperactivity and stereotypy will be quantified following systemic and intracranial administration of 5-HT agonists and antagonists as well as 5-HT lesions. Single unit recording, microiontophoresis and stimulation techniques will be used to characterize the cellular effects of cocaine on 5-HT-containing DR and MR neurons which project to DA neurons of the ventral tegmental area (VTA) or their limbic terminals in accumbens. We will also analyze the electrophysiological effects of 5-HT on DA- containing VTA neurons and assess whether cute and chronic cocaine modifies the normal action of 5-HT on DA neurons. Importantly, the experiments in this proposal are designed to provide basic information about 5-HT.DA interactions and ultimately may reveal how these interactions are altered by cocaine, perhaps suggesting new strategies for pharmacological intervention in abusers.
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