The euphoric properties of psychomotor stimulants impart a powerful reinforcing action to these agents which may underly their strong potential for abuse in humans. The rewarding properties of CNS stimulants in general and cocaine in particular appear to be due, in part, to their ability to increase neurotransmission at dopaminergic (DA) synapses. Much of what is currently known about the mechanism of action of cocaine on DA transmission is derived from pharmacological studies evaluating cocaine's actions on DA systems not directly involved in the process of stimulant self administration. Since it is now appreciated that midbrain DA systems are not homogenous and possess a number of different biochemical, physiological and pharmacological properties, the relevance of prior studies investigating the interaction of cocaine with DA systems to the larger issue of cocaine abuse is unclear. The proposed project involves a combined electrophysiological and biochemical approach to evaluate the effects of cocaine on mesotelencephalic DA neurons in rodents. In the first group of experiments, extracellular single unit recording and microiontophoretic techniques will be used to determine whether antidromically identified DA neurons differ in their response to locally or parenterally administered cocaine. Biochemical studies will be conducted in parallel to assess alterations in DA metabolism in and release from selected mesotelencephalic systems. Findings will be correlated with alterations in neuronal firing evaluated by single cell recording. In a second group of experiments, biochemical and electrophysiological techniques will be employed to study the effects of cocaine on DA target neurons in regions thought to participate in stimulant self-administration (e.g. nucleus accumbens, prefrontal cortex) and compared with the non-rewarding DA projections to the DA receptive neurons in striatum. In both groups of experiments, comparisons will be made between cocaine and other drugs exhibiting similar pharmacological properties but differing in their ability to sustain self-administration. If cocaine is observed to elicit significant and selective effects on the functioning of certain DA systems or postsynaptic follower neurons, attempts will be made to prevent or reverse these electrophysiological and neurochemical effects pharmacologically. By more clearly understanding the pharmacological actions of cocaine on specific DA neurons and their follower cells, we may gain further insight into the neural mechanisms underlying cocaine's reinforcing properties and identify strategies for reversing or preventing these actions.
