RECEPTOR MECHANISMS IN MOVEMENT DISORDER PATHOPHYSIOLOGY

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The basal ganglia play a major role in the control of normal movement and coordination. Lesions of the basal ganglia result in movement disorders ranging from severe akinesia, rigidity and tremor to dystonia, chorea and ballismus. The symptomatology in any particular individual or disease process depends on the distinct subgroups of neurons affected. The inhibitory amino acid GABA, is the neurotransmitter for the vast majority of striatal, pallidal and substantia nigra neurons, excitatory amino acids (EAA) such as glutamate serve as the neurotransmitters for cortical and thalamic efferents to striatum, subthalamic nucleus and substantia nigra neurons, dopamine is the neurotransmitter of the nigrostriatal pathway, and many striatal neurons bear adenosine A2 receptors. In the last several years molecular biologic advances have allowed the genes for many receptor subtypes to be cloned. This makes it possible to determine the distribution and regulation of these newly cloned receptor subtypes in specific basal ganglia neuronal types and their role in the pathophysiology of the movement disorders. This proposal for a program project is a collaborative, multicenter effort to study the role of the newly cloned receptor subtypes in animal models of movement disorders. Project 1 will determine if the excitatory amino acid receptors are preferentially localized on the neurons which degenerate in Huntington's disease and how the expression of amino acid receptor genes change in animal models of movement disorders. Project 2 will study the location of dopamine receptor subtypes in striatum, cortex and globus pallidus. Project 3 will study the regulation of adenosine A2 receptors at the molecular level in animal and human, and the receptor's role in animal models of movement disorders. Project 4 will study the factors by which amino acid and dopamine receptors affect immediate early gene expression in animal models of movement disorders. Project 5 will study the possibility that oxidative phosphorylation defects may play a role in the pathogenesis of Huntingtons's and Parkinson's diseases by processes leading to slow excitotoxic neuronal degeneration. These projects will be supported by administrative, antibody production and animal surgery cores. Elucidation of the details of receptor regulation in animal models of human disease will provide a more complete understanding of basal ganglia circuitry in health and disease and allow the rational development of pharmacotherapies for these illnesses using drugs selective for the various receptor subtypes.