Parkinson's Disease (PD) is a devastating movement disorder consequent to massive death of neurons in the substantia nigra. An important functional consequence of this cell death is depletion of the neuromodulator dopamine (DA) within the striatum. In addition to the DA input, the striatum also receives major glutamate input from the cerebral cortex and thalamus. The ameliorative effects of DA agonists in animal models of PD are potentiated by antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. In addition, NMDA antagonists block the appearance of dyskinesias in Parkinsonian animals treated with DA agonists and also block DA agonist and antagonist-induced immediate early gene expression in the intact striatum. Recent data from our laboratory indicate that distinct NMDA receptors selectively interact with Dl and D2 DA receptors to regulate immediate early gene expression in striatonigral and striatopallidal efferent neurons in both DA-depleted and intact animals. Furthermore, evidence suggests that corticostriatal and thalamostriatal afferents selectively affect the function of D2 receptor-containing striatopallidal and Dl receptor-containing striatonigral neurons, respectively. Finally, data from studies on other brain regions indicate that different NMDA receptor subtypes can be targeted to synapses associated with distinct afferent pathways within the same neuron. Thus, the goal of this proposal is to test the hypothesis that Dl and D2 dopamine receptors selectively interact with distinct NMDA receptors by virtue of the afferent-selective expression of distinct post-synaptic NMDA receptors in striatal efferent neurons. This hypothesis will be tested by completing the following specific aims: A) Establish how generalized the selective association of specific NMDA and DA receptors is across striatal efferent neuron responses. B) Determine the pharmacology of NMDA receptors mediating corticostriatal and thalamostriatal activation of immediate early gene expression in striatal efferent neurons in vivo and examine the modulation of this activation by DA receptor manipulations. C) determine the kinetics and pharmacology of NMDA receptor-mediated EPSCs evoked in striatal efferent neurons by activation of cortical and thalamic afferents and examine the modulation of those EPSCs by DA receptor manipulations. It is anticipated that the results of these experiments will provide new insight into the functional relationship between DA and NMDA receptors in the regulation of striatal efferent neurons and will lead to important new advances in therapeutic interventions for the treatment of PD and other disorders of the basal ganglia.
