Cocaine is undergoing an epidemic of abuse in the US; however, little is known concerning the neural mechanisms which lead to the abuse of stimulants. Using a neuroanatomical approach, these studies will test the hypothesis that cholinergic interneurons represent an integral pathway in nucleus accumbens. This pathway is likely to be critical for the expression of the reinforcing properties of cocaine and other stimulants. Progress along these lines will contribute important knowledge to the broader issue of the neurobiological substrates underlying drug abuse and addiction. This type of information will provide the basis for targeting multiple pharmacological sites and devising rational therapeutic strategies. The specific aims of the proposal are: 1) To test the ability of cocaine to modulate dopamine receptors in the nucleus accumbens and striatum. Quantitative receptor autoradiography will be used to examine the dopamine D-1 and D-2 receptor subtypes in the nucleus accumbens after acute and repeated cocaine administration. These findings will confirm and extend prior reports that the nucleus accumbens possesses a unique neural response to cocaine. 2) To examine whether lesions of the allocortical afferent pathways to the nucleus accumbens affect the D-2 dopamine receptor response to cocaine. Afferent pathways to the nucleus accumbens from the hippocampus and amygdala will be lesioned in order to determine whether the D-2 binding sites are localized to intrinsic neural populations. It is predicted that lesions of afferent pathways will not alter the D-2 receptor response to cocaine. 3) To demonstrate that interneurons of nucleus accumbens are the site of cocaine-induced changes in D-2 receptor loss. It is predicted that the D-2 receptors which are localized to intrinsic neurons of the nucleus accumbens will be lost, thereby abolishing the response of D-2 receptors to cocaine. 4) To determine whether the effects of cocaine of D-2 receptors are linked to cholinergic interneurons in the nucleus accumbens. In situ hybridization for D-2 receptor mRNA and immunocytochemical staining of cholinergic and GABAergic interneurons will be combined to directly identify the cellular localization of D-2 receptors. It is predicted that D-2 receptors will be localized to cholinergic interneurons in the nucleus accumbens. These studies will examine the regulation of the D-2 receptor by cocaine at the molecular (mRNA) level.