The work proposed focuses on interrelated regions of the basal ganglia (striatum and pallidum) and substantia nigra. Diseases of the basal ganglia are debilitating and are associated not only with motor dysfunctions but also cognitive-affective symptoms. The main goal of the proposed work is to gain an understanding of the functional organization of the basal ganglia and its dopamine- containing input systems in the primate and to relate findings from experiments on normal and MPTP-treated primates to observations on postmortem human brains from normal individuals and from persons who suffered premortem extrapyramidal disorders such as Parkinson's disease, progressive supranuclear palsy and Huntington's disease. Experiments are proposed to study the distribution of neurotransmitter-related compounds in the striatum, pallidum and substantia nigra and to relate the chemoarchitecture of these regions to their input-output connections. Special emphasis is to be placed upon the cholinergic and dopaminergic mechanisms of the basal ganglia, on the neuropeptide-containing elements there, and on neuroleptic- related sigma receptor sites insofar as they are related to the dopamine-containing nuclei of the midbrain. Studies are planned to extend these observations by monitoring the effects of in vivo pharmacological manipulations. By coordinating observations in monkey and human, it is hoped that significant progress can be made toward an understanding of the basal ganglia in health and disease.
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