The long-range objective of this project is to characterize the behavioral and neurochemical effects of cocaine in nonhuman primates and to identify drugs that may have therapeutic value in treating stimulant abuse. Methods include schedule-controlled behavior as an index of CNS activity, intravenous self-administration of drugs as indicative of reinforcing efficacy or abuse liability, drugs as discriminative stimuli controlling behavior, and in vivo microdialysis techniques to allow for the measurement of direct neurochemical changes associated with drug effects on behavior. Efforts during the past year have focused on pharmacological manipulation of the serotonin system to assess changes in sensitivity to the CNS effects of cocaine. Administration of drugs that increase serotonergic activity reliably attenuated the behavioral-stimulant and reinforcing effects of cocaine. Moreover, drug interaction studies indicated that the serotonin system can provide inhibitory modul ation of psychomotor stimulants with selective dopaminergic actions. The latter results suggest that serotonergic modulation of cocaine and related abused stimulants may involve direct interactions between serotonin and dopamine. Cocaine and related dopamine transport blockers also caused pronounced increases in extracellular dopamine, and the drug potency and time course of action corresponded closely to drug-induced changes in schedule-controlled operant behavior. Collectively, these data indicate that the serotonin system may be an effective target for the treatment of cocaine abuse.
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