Dopamine (DA) has been implicated in the pathophysiology of schizophrenia, and multiple lines of evidence suggest that certain neocortical regions may be sites of dysfunction in this disorder. However, until recently, relatively little is known about the organization of DA projections to the expanded and highly differentiated neocortex of primates. Studies conducted during the currently funded award, in concert with investigations by others, have demonstrated that the anatomical and molecular characteristics of DA projections to neocortex are substantially different in monkeys than in rodents, that the DA innervation of monkey cortex is highly specialized and distinctive in relation to other elements of neocortical circuitry and that the DA innervation of monkey neocortex accurately predicts the organization of that system in human neocortex. Findings from these studies have also suggested that mesocortical DA projections in primates are heterogenous, and may be composed of at least two distinct classes of DA axons. Consequently, the studies proposed in this application will test the hypothesis that the separate classes of DA axons in primate cerebral cortex differ 1) in their regional and laminar patterns of distribution; 2) in the isoform of TH that they utilize; 3) in their patterns of development and maturation; 4) in the anatomical and molecular features of their neurons of origin; 5) in their relation to the cholecystokinin and neurotensin neuropeptide systems; 6) in their neuronal targets in the cerebral cortex; 7) in the DA receptor subtypes with which they interact; and 8) in their relative vulnerability to the neurotoxin MPTP. Where possible, these studies will be extended to investigations in human brain in order to determine the extent to which these distinguishing features of mesocortical DA projections in monkeys are present in humans. Understanding the unique characteristics of these classes of DA cortical axons will make possible the generation of testable hypothesis regarding the role of each DA systems in normal cortical function in primates and in the pathophysiology of schizophrenia and other disorders.
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