NMDA RECEPTOR FUNCTION IN NEUROCHEMISTRY OF PARKINSONISM

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A hyperglutamatergic state secondary to dopamine (DA) loss has been suggested to exist in Parkinson's disease (PD). By examining the effects of treating both neurochemical pathologies (DA degeneration and hyperglutamatergic activity) of this disease, the results of experiments described herein will contribute relevant and necessary neurochemical data to a body of literature suggesting the N-methyl-D- aspartate (NMDA) receptor blockade has anti-Parkinsonian effects. Proposed studies will examine the role of this glutamate receptor subtype tin the neurochemistry of intact and DA-denervated striatum. In vivo microdialysis and high performance liquid chromatography with electrochemical detection will be used to monitor striatal extracellular DA and acetylcholine (Ach) in freely-moving rats. Unilateral 6-hydroxydopamine lesions will serve as an animal model of PD. Levodopa (L-DOPA), the precursor of DA, is the most effective means for reversing Parkinsonian symptoms, except after chronic administration, at which point deleterious behavioral side effects arise. This effect of chronic L-DOPA is thought to be due to the lack of a neurochemical balance in striatum which is important for the processing of sensorimotor information by the basal ganglia. Experiments in this proposal will test the ability of MD-801, a non- competitive NMDA receptor antagonist, and L-DOPA to collectively restore the balance between DA and Ach (an index of excitatory drive to striatum) in the DA-denervated striatum. Conclusions from these studies will provide insight to the neurochemical etiology of PD and also to the potential viability of NMDA receptor antagonism in the treatment of this disease.