The long-term objectives of the project are to assess and determine the mechanism underlying the metabolic and pharmacologic effects of cocaine in neuronal circuits related to the rat nucleus accumbens (NAc), a critical dopaminergic reward region, during chronic treatment and early abstinence. The therapeutic potential of dopamine agonists on metabolic recovery during abstinence will be evaluated, allowing a better understanding of beneficial therapies for cocaine abuse.
The specific aims of the project are (1) to characterize the effect of chronic cocaine treatment on functional activity in NAc using markers for glucose utilization and pharmacologic receptors affected by cocaine in this region, (2) to determine the mechanism of chronic cocaine-induced differential activation of NAc, (3) to assess the magnitude and time course of selective reduction of functional activity in NAc during cocaine abstinence, and (4) to study the putative enhancement of metabolic recovery induced by dopamine agonists during this period. The quantitative [14C]2-deoxyglucose (2DG) autoradiographic method will be employed to examine the effect of chronic cocaine treatment on glucose utilization in brain circuits related to the NAc, and following selective neuronal and neurochemical lesions in brain regions, such as medial prefrontal cortex, which are demonstrated to project to the affected portions of NAc. Thus, the underlying mechanism of these metabolic effects of cocaine will be elucidated. Correlation of these regional metabolic data with the results of studies of chronic cocaine treatment on regional dopamine and opiate receptor levels using in vitro receptor autoradiography in adjacent sections from the same brain tissue will further elucidate the underlying mechanism. The effect of pharmacotherapy with dopamine agonists during cocaine abstinence on NAc metabolism will also be investigated using the 2DG method. Together, these studies will determine how chronic cocaine treatment causes NAc metabolic alteration, and will test pharmacotherapeutic efficacy following chronic cocaine use.
