This program project for Neuroscience Work Groups in Mental Health will be carried out at New York University Medical Center and Karolinska Institute, Stockholm, and will investigate the role of dopaminergic and peptidergic neuronal systems in CNS function in physiological and pathological states. The anatomical, biochemical and physiological heterogeneities of the dopamine (DA) neurons will be studied. Immunohistochemistry, in combination with in situ hybridization and retrograde tracing, will be used for studies on localization and cellular differentiation of DA and specific neuropeptides, as well nontransmitter proteins. These three procedures represent complementary methodology and are much more powerful in combination than any one alone. The colocalization of DA with other transmitter and nontransmitter substances will identify distinct subsets of DA neurons, and may serve as a marker for specific subsets of DA neurons which share certain regulatory mechanisms. It will be possible to quantitatively establish differences in tyrosine hydroxylase (TH) mRNA in different DA populations and define the rate of expression of TH in different midbrain DA cells in relation to coexistent peptides. The differences in responsiveness to acute and chronic neuroleptic treatment may be attributable to the density of autoreceptors regulating synthesis and/or release of DA in different forebrain DA innervation. It may therefore be possible to define distinct populations of midbrain DA neurons on the basis of immunohistochemical staining for the D2 DA receptor binding sites. Furthermore, the mechanisms involved in the desensitization of various DA receptor subtypes will be investigated and the coupling between D1 DA receptor binding protein and adenylate cyclase in postmortem non-schizophrenic and schizophrenic brain will be studied.