Effects of maternal lead exposure on central nervous system maturation in postnatal rats.

The striatum receives dopamine (DA) and glutamate inputs which synapse on spiny efferent neurons. Glutamate acting via N-methyl-D-aspartate NMDA and non NMDA receptors regulates the firing of striatal efferent neurons, whereas D1 DA receptors modulate the responsiveness of these neurons to glutamate input. Studies indicate that DA depletion alters both NMDA and D1 DA receptor function in the striatum Thus, this thesis tested the overall hypothesis that DA-depleting brain lesions alter the interactions between NMDA receptors and D1 DA receptors, and thus the regulation of the striatonigral pathway when compared to neurologically intact animals. The overall hypothesis was tested by achieving the following specific aims. In specific aim 1, we examined the expression of the NR2A subunit of the NMDA receptor in striatonigral and striatopallidal neurons after unilateral DA depletion. Our results showed an increase in the NR2A subunit mRNA in both populations of striatal efferent neurons. As a consequence of DA depletion, therefore, the subunits from which NMDA receptors in striatal efferent neurons are composed are altered. In specific aim 2, we examined the effects of systemic NMDA receptor blockade by NM-801 on D1-agonist-induced immediate early gene (IEG) expression in the DA depleted striatum and provided evidence for decreased NMDA receptor involvement in D1-mediated gene regulation. In specific aim 3, we went on to further evaluate whether D1 DA receptor mediated EEG expression is differentially modulated by administration of distinct types of NMDA receptor antagonists in the DA-depleted striatum. Our results demonstrate that CGS 19755, which blocks both NR2A- and NR2B-containing NMDA receptors, suppressed D1-mediated <italic>c-fos