Alterations in the function of striatal neurons projecting directly (striatonigral) and indirectly (Striatopallidal) to basal ganglia output nuclei contribute to motor dysfunctions associated with neurological disorders such as Parkinson's disease. Recent finding suggest that antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor may be effective in treating Parkinsonism. NMDA receptors in striatum receive excitatory input from cortex, and are comprised of multiple subunits, the expression of which determines the pharmacology of the receptor. For example, inclusion of the 2a subunit confers an """"""""antagonist-preferring"""""""" profile to the receptor, whereas inclusion of the 2b subunit produces one that is """"""""agonist-preferring."""""""" These two NMDA receptor subunits how different regional distributions in striatum. The implications of these differences in pharmacology and regional distribution for the functioning of the basal ganglia are unknown. Some data suggests that NMDA receptor antagonists that distinguish between subtypes of NMDA receptors have differential effects on striatal neuron function. This proposal will test the hypothesis that blockade of specific subtypes of the NMDA receptor, either alone or in combination with dopamine receptor manipulation, will have differential effects on striatal efferent function. First, the expression of the 2a and 2b subunits by defined striatal neuron populations will be determined using in situ hybridization histochemistry with double labeling. Second, different classes of NMDA receptor antagonists will be given over a range of doses to both intact and dopamine-depleted rats to determine how blockade of different subtypes of NMDA receptors affects the function of striatal efferent neurons. The antagonists will be given alone and in combination with D1- and D2-dopamine receptor agents, which selectively affect striatonigral and striatopallidal neurons, respectively. The techniques of in vivo microdialysis and in situ hybridization histochemistry will be combined to measure GABA and neuropeptide release from, and immediate early gene expression in, the two striatal efferent pathways as measures of striatal neuron function. Clarifying the relation between NMDA receptors and striatal efferents will improve our understanding of cortical influences on basal ganglia function and may contribute to the development of more effective therapies for disorders of basal ganglia, such as Parkinson's disease.
