The major objective of the proposed research is to determine the effects of chronic exposure to cocaine (in rats) on the function of neural circuitry involving the substantia nigra. In particular, dynamic in vivo interactions between dopaminergic transmission and GABA-containing outputs from the basal ganglia will be examined in order to define how chronic exposure to cocaine modifies these interactions. For these studies, we will make measurements indicative of the turnover rate a) of GABA in specific pathways (nigrotectal and nigrotegmental) which are known to mediate the expression of certain behaviors elicited by dopamine stimulants such as cocaine and b) of dopamine in the nigrostriatal pathway. The neurotransmitter turnover in these pathways will be manipulated using the following probes: a) directly and indirectly-acting dopamine agonists given either systemically or directly applied to specific intracerebral sites and b) serotonergic agonists and antagonists applied directly into substantia nigra. The effect of these probes on transmitter turnover will be evaluated in rats chronically exposed to cocaine in comparison to drug-naive rats. Using turnover as an index of the functional responsiveness of the nigral outputs to selected neurotransmitters in the nigrostriatal circuit, we hope to identify those synaptic links that are functionally altered by chronic exposure to cocaine. An attempt will be made to relate neurochemical changes observed to each other and to changes in behavioral responses. In particular, we hope to identify functional neurochemical alterations that may account for the behavioral sensitization to cocaine in chronically exposed animals. As sensitization to psychomotor stimulants in animals may be a model of exaggerated psychotogenic actions of these drugs in chronic stimulant abusers (8), it is possible that the information we obtain may provide insights into the neuropathological basis for behavioral disorders induced by stimulant abuse.