The central dopamine (DA) system has been implicated in the pathophysiology of both Parkinson's disease (PD) and schizophrenia, as well as in the neuropharmacology of drug abuse. In the case of PD, cellular pathology of the nigro-striatal pathway has been defined, although the extent to which the cortical DA systems are disrupted in PD remains controversial. The situation with schizophrenia is similar in that although DA antagonists are useful in alleviating symptoms, the degree to which structural pathology exists in the DA innervation of cortex is not clear. Our ability to develop testable hypotheses on the relative contributions of disruption of striatal and/or cortical DA systems in neurologic diseases and drug abuse has been greatly hampered by the lack of precise data on the anatomic organization of cortical DA systems in primate. This limitation also makes it difficult to determine the potential role of the cortical dopamine system in normal functions, such as cognition. More specifically, investigators in the area have yet to make the transition from an understanding of cortical DA innervation that is based on preferred layers and regions to a cellular/synaptic model that is integrated into modern concepts of cortical organization. Recent advances in molecular neurobiology and neuroanatomy have occurred that make such a transition feasible. We have hypothesized that the pyramidal cells that furnish key corticocortical projections are a primary DA target neuron in association and limbic cortices. The experiments outlined in this proposal will test this hypothesis and in the process develop a synthetic model of DA innervation that integrates the distribution of pre-synaptic DA markers (i.e., terminals) with post-synaptic DA markers (i.e., receptors). This integration will occur on regional, laminar, cellular, and sub-cellular levels. Riboprobes and antisera will be prepared against specific DA receptor subtypes, and the density and distribution of these receptors will be quantified in respect to specific cortical regions and layers. The density of DA terminal varicosities will also be quantified, and analyzed ultrastructurally. In addition, methods combining retrograde transport, cell loading, and immunocytochemistry will be used to map out the distribution of all three receptor subtypes and incoming DA terminals along the dendritic tree of corticocortically projecting neurons with a known efferent target. These data will allow for the putative role of DA in neurologic disease, drug abuse, and normal brain function to be analyzed and conceptualized within the framework of precisely defined cortical circuits that are amenable to further anatomic, physiologic and behavioral dissection.
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