Substantia nigra glutamate antagonists produce contralateral turning and basal ganglia Fos expression: interactions with D1 and D2 dopamine receptor agonists.

Abstract

Experiments measuring behavior and immediate-early gene expression in the basal ganglia can reveal interactions between dopamine (DA) and glutamate neurotransmission. Nigrostriatal DA projections influence two striatal efferent pathways that, in turn, directly and indirectly influence the activity of the substantia nigra pars reticulata (SNr). This report tests the interactions between striatal DA receptors and nigral glutamate receptors on basal ganglia function by examining both contralateral turning and Fos immunoreactivity in striatum and pallidum following unilateral intranigral microinfusions of glutamate antagonists given to intact and 6-OHDA-lesioned rats. The NMDA antagonist AP5 (1 microg), or the AMPA/kainate antagonist DNQX (0.015-1.5 microg), injected into the SNr (0.5 microl) elicited contralateral turning as well as both striatal and pallidal Fos expression. Moreover, intranigral DNQX elicited more turning and greater numbers of Fos-positive striatal neurons in 6-OHDA-lesioned animals than in unlesioned controls, suggesting that the 6-OHDA injection induces functional changes in nigral glutamate transmission. In 6-OHDA-lesioned rats, systemic injections of the DA D1 receptor agonist SKF38393 (0.5 mg/kg, i.p.) increased striatal Fos expression due to intranigral DNQX. In contrast, the D2 agonist quinpirole (0.1 mg/kg, i.p.) decreased striatal Fos expression but increased the pallidal Fos arising from intranigral AP5. In additional experiments, both intact and 6-OHDA-lesioned rats were given simultaneous intranigral and intrastriatal infusions and turning and pallidal Fos expression were measured. 6-OHDA-lesioned rats given 5 microg of intrastriatal quinpirole exhibited both turning and pallidal Fos that was significantly increased by intranigral AP5. These results indicate that the opposing influences of D2 agonists and endogenous nigral glutamate transmission are mediated by striatal D2 receptors. Finally, the behavioral effects of intranigral glutamate antagonism can be dissociated from the effects on striatal or pallidal immediate-early gene expression.