The specific aims are to establish the relationship among PCP, sigma, and neuropeptide Y (NPY) receptors in regulation of dopamine release and second messenger systems in the nucleus accumbens. Elevation of dopamine levels in the nucleus accumbens is generally accepted as the neurochemical substrate for reinforcement. We hypothesize that the physiological effects of PCP, mediated by each of the various receptors at which it binds, can be discriminated by the use of selective ligands for these sites. Furthermore, we hypothesize that NPY acts as an endogenous ligand at a subtype of sigma receptor and can be used to distinguish regulatory processes of dopamine release mediated by a receptor subtypes. By measuring physiological responses to PCP, MK-801, prototypical sigma ligands, and NPY in brain tissue, we will establish effects of these systems on gross, integrative processes. To determine effects at the cellular level, we will use PC12 cells, which can be differentiated to a neuronal, dopaminergic phenotype by treatment with NGF, and which bear sigma and NPY, but not PCP, receptors. With these methods, we intend to distinguish effects of PCP mediated by sigma and PCP receptors.
