Declining efficacy of striatal dopamine replacement with L-DOPA in advanced Parkinson's disease (PD) has led to the introduction of direct acting dopaminergic agonist drugs. In spite of the use of such agents, many patients with advanced PD experience only minimal response to agonist drugs. Neurophysiological evidence suggests that striatal output through the globus pallidus and nigra is mediated by a series of inhibitory neuronal synapses which use GABA as the neurotransmitter. PD patients have deficiencies of glutamic acid decarboxylase (GAD) activity in their basal ganglia nuclei, and those with advanced PD have lowered CSF concentrations of GABA. Thus, striatal GABA dysfunction may arise concomitant with worsening of PD, and may be responsible for therapeutic difficulties encountered in these patients. The experiments in this proposal will address two questions. First, what is the effect of striatal dopamine depletion upon GABA synaptic functions within the basal ganglia? Animals will have selective unilateral reductions of striatal dopaminergic input brought about by stereotactic peri-nigral injection of 6-hydroxydopamine. At various times after lesioning, presynaptic GABA markers, including GAD activity, GABA levels, and high-affinity nerve terminal GABA transport will be assayed in various brain regions including striatum. Synaptic GABA receptor binding will be studied with quantitative ligand binding autoradiography, utilizing radiolabeled flunitrazepam and muscimol as ligands. Additionally, regional GABA turnover rates will be estimated utilizing a steady-state technique which involves the intraventricular administration of radiolabeled GABA precursors. Second, what are the effects of augmentation or reduction of striatal GABA synaptic activity upon dopamine metabolism within the striatum, and upon the functional effects of striatal dopamine receptor stimulation? Unilateral augmentation or reduction of GABA synaptic activity within the striatum will be brought about by microinjection of GABA synaptic agonists or antagonists respectively, and (1) dopamine turnover will be estimated following intraventricular perfusion of radiolabeled tyrosine, and (2) changes in cerebral metabolism brought about by striatal dopamine receptor stimulation will be examined using the 2-deoxyglucose autoradiographic technique. If the consequences of striatal dopamine receptor stimulation are adversely affected by reduced striatal GABA synaptic activity, then pharmacological augmentation of striatal GABA synaptic activity could be rationally proposed for patients with advanced PD.
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