DESCRIPTION (provided by applicant): Diseases affecting the basal ganglia produce a variety of movement deficits, and these deficits are often totally disabling. Parkinson's disease, which affects about 1.5 million Americans, is a basal gangliar disease that leads to tremor, decreased spontaneous movement and slowness of voluntary movement. Drug treatment of Parkinson's disease with L-DOPA is only partially effective in relieving the motor symptoms of the disease, and prolonged drug treatment leads to severe side effects such as uncontrollable involuntary movements. Deep brain stimulation at specific sites in the basal ganglia can provide effective relief of Parkinson symptoms. Neither drug treatment nor deep brain stimulation restores damaged neural circuitry in the basal ganglia. Therefore, it is likely that these therapies prevent abnormal basal gangliar output from disrupting processing in other structures related to movement control. One major neural structure related to movement control is the cerebellum, but there are no direct connections between the cerebellum and the basal ganglia. We have discovered that disrupting activity in the cat red nucleus, which connects cerebellar output to the spinal cord, can produce motor symptoms that are strikingly similar to those of Parkinson's disease. The general hypothesis underlying this proposal is that motor deficits produced by basal gangliar disease are mediated by pathways that allow basal gangliar output to disturb processing in structures related to the cerebellum. Specifically, we hypothesize that basal gangliar output from the cat entopeduncular nucleus affects activity of cells in zona incerta, which affects activity of cells in the red nucleus. Our experiments will: 1. Identify regions in the related nuclei that contain cells related to forelimb movement. 2. Determine how these forelimb regions affect movement with activation and inactivation by injection of receptor antagonists. 3. Develop an acute and chronic cat model of basal gangliar disease to test critical aspects of the hypothesis. 4. Identify additional brainstem pathways that allow basal gangliar output to influence cerebellar circuits. The results will provide a deeper understanding of how the basal ganglia and cerebellum interact to control limb movements and will lead to new approaches for the treatment of movement disorders.