During the past decade, cocaine abuse has become this nation's most devastating drug problem. The potent rewarding effect of cocaine, more than any other variable, probably accounts for the meteoric rise in cocaine abuse. Animal studies have demonstrated that the dopamine (DA)-containing neuronal tracts arising from the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) and medial prefrontal cortex (MPC) are intricately involved in the rewarding efficacy of cocaine. The objectives of this research program are to identify the neuronal mechanisms by which cocaine alters activity within these systems, the neuronal circuitry affected by cocaine's actions and the influence of repeated administration of cocaine on such circuits. Electrophysiological studies from this laboratory have determined that cocaine only partially inhibits the firing of A1O DA neurons within the VTA while potently inhibiting the activity of target neurons within the NAc and MPC. This profile is unlike that of other DA agonists and indicates a poor compensatory decrease of DA activity following enhanced activation of postsynaptic DA receptors resulting from cocaine administration. These findings have lead to the hypothesis that the poor compensatory response results in exaggerated dopaminergic activity which may be related to cocaine's reward efficacy. The present proposal outlines a research plan which will utilize single-cell recording, microiontophoresis, electrical stimulation and radiolabelled dopamine uptake techniques to identify the mechanisms, including the DA receptor subtypes and serotonergic interactions, by which cocaine exerts this unusual profile of effects. In addition, experiments using antidromic stimulation techniques are proposed which should identify the efferent neuronal pathways affected by cocaine's actions within the mesoaccumbens and mesocortical DA pathways. Upon identification of such circuits, additional experiments will determine the extent to which other drugs of abuse affect the same pathways. Finally, experiments will attempt to identify the alterations occurring in the mesoaccumbens and mesocortical DA pathways as a result of repeated cocaine administration. It is hoped that the results of these experiments will define the neurobiological concomitants of cocaine use, particularly as they relate to reward mechanisms and will provide information regarding the consequences of long-term
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