Intraneostriatal administration of glutamate antagonists increases behavioral activation and decreases neostriatal ascorbate via nondopaminergic mechanisms.

Behavioral findings suggest that the effects of neostriatal glutamate and ascorbate are opposed to those of neostriatal dopamine. Recent evidence also indicates that glutamate and ascorbate are linked via a carrier-mediated heteroexchange process, suggesting that ascorbate may act through the glutamate system to influence behavior. In order to assess glutamate-ascorbate interactions and their influence on the behavioral output of the basal ganglia, glutamate and homocysteic acid (a glutamate reuptake blocker) as well as NMDA antagonists were infused into the neostriatum of freely moving rats while extracellular neostriatal ascorbate was monitored via electrochemically modified carbon-fiber electrodes. Neostriatal 3,4-dihydroxyphenylacetic acid (DOPAC), a major dopamine metabolite, also was recorded in order to assess the dependency of any drug effect on the nigrostriatal dopamine system. Intraneostriatal infusions of L-glutamate (1 micrograms/microliters), but not L-homocysteic acid (30 micrograms/microliters), elevated extracellular neostriatal ascorbate levels. Neither of these drugs had any effect on neostriatal DOPAC or overt behavioral activity. Intraneostriatal infusion of the noncompetitive NMDA antagonist dizocilpine (MK-801; 3 micrograms/microliters) or the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonene (CPPene; 5 micrograms/microliters) decreased neostriatal ascorbate but had no effect on neostriatal DOPAC. Both dizocilpine and CPPene activated behavior in intact and sham-lesioned animals as well as in animals with near-total depletions of neostriatal dopamine following a 6-hydroxydopamine lesion. When administered systemically, however, dizocilpine (1.0 mg/kg) significantly increased neostriatal DOPAC. This effect appears to be regulated via midbrain NMDA receptors, in that this effect was completely abolished by electrolytic lesions of the substantia nigra pars reticulata.(ABSTRACT TRUNCATED AT 250 WORDS)