The overall purpose of the research program is a further understanding of the neurochemical basis of drug abuse. In particular, the experimental approach consists of two objectives: 1) To gain insight into the regulatory functions of the neuronal systems that mediate drug reinforcement, and 2) to determine the effects of repeated exposure to either cocaine or amphetamine on these systems. It is anticipated that the convergence of these two strategies will generate knowledge required for the rationale development of clinically useful, therapeutic agents capable of decreasing the craving and or reward associated with drugs of abuse. The proposed studies constitute a program to examine the interaction of serotonin and dopamine with each other and their response to drugs of abuse such as cocaine, amphetamine, and MDMA. The studies involve protocols to examine transmitter release and synthesis utilizing brain slices (in vitro) and microdialysis (in vivo). The specific objectives set forth to investigate the above issues are: A) What is the pharmacological basis mediating the serotonin (5HT)- facilitation of dopamine (DA) release at the level of the nerve terminal. Additionally, experiments are designed to elucidate the second messenger system of the 5HT receptor and to determine potential involvement of either potassium or calcium fluxes. Subsequent experiments focus on the role of endogenous 5HT on DA release, and systemically administered 5HT agonists on both DA release and synthesis. Finally, does chronic cocaine alter the efficacy of 5HT to facilitate DA release. B) The second major goal of the proposal tests the possibility that DA autoreceptors are the functional counterpart of the recently discovered D3 receptor. In vitro (brain slices) and in vivo protocols are presented to characterize the pharmacological actions of selective DA agonists and antagonists at DA autoreceptors. Lastly, experiments are proposed to discover if repeated exposure to either cocaine or amphetamine modify the functional responsivity of nerve terminal DA autoreceptors.