DESCRIPTION: The proposed research program focuses on the interactions between dopamine (DA) and excitatory amino acid (EAA) transmitters within the nucleus accumbens (Nac), a basal forebrain structure that is considered a limbic component of the striatal complex. DA receptors within the Nac have been a central focus of research into the mechanisms of both drugs of abuse and antipsychotic drugs, and accordingly, previous work by the investigator has concentrated on the roles and interactions of DA receptor subtypes in regulating the activity of Nac neurons, and how such regulation is altered by chronic administration of cocaine and other drugs of abuse. Since recent hypotheses regarding mediation of drug self-administration, psychomotor stimulant sensitization, and schizophrenia have suggested an important role of EAA/DA interactions, the present proposal outlines a series of experiments designed to study (1) the pharmacological nature of EAA receptors on NAc neurons; (2) how such EAA receptors might interact with one another; and (3) the interaction of EAA-receptors with DA receptors. In addition, the interactions between receptors will be studied after repeated administration of cocaine. The investigator proposes to study these mechanisms using traditional in vitro current and voltage clamp procedures in NAc slice preparation, and whole cell patch clamp procedures in acutely dissociated NAc neurons. The investigator has consulted with established laboratories and has arranged for them to help in the development of the in vitro procedures in his laboratory. The Subcommittee anticipates that such techniques will be successfully developed over the five year period of this award and will allow the investigator to address important questions of neuronal regulation at a more mechanistic level of analysis.