Regulation of NMDA-stimulated [C-14]GABA and [H-3]acetylcholine release bystriatal glutamate and dopamine receptors

Striatal function is heavily influenced by glutamatergic and dopaminergic a fferent input. To ultimately better understand how the N-methyl-D-aspartate (NMDA) antagonist, phencyclidine (PCP), alters striatal function, we sough t to determine how NMDA receptor function is influenced by activation of ot her glutamatergic receptors and by dopaminergic receptors. To this end, we used NMDA-stimulated efflux of [C-14]GABA and [H-3]acetylcholine (ACh) from striatal slices to assess the influence of these receptors on NMDA functio n. NMDA-stimulated [C-14]GABA release was more sensitive to NMDA and glycin e antagonists than was [H-3]ACh release, suggesting that different NMDA rec eptors regulate the release of these neurotransmitters. Furthermore, NMDA-s timulated [H-3]ACh release was inhibited by a D-2 receptor mechanism wherea s NMDA-stimulated [C-14]GABA release was enhanced by D-1 receptor activatio n. NMDA and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide (AMPA) interact additively to evoke [H-3]ACh release, and syne rgistically to evoke [C-14]GABA release. An additive effect of NMDA and kai nate (KA) was found on [C-14]GABA release, but NMDA and KA. acted in a less than additive manner in evoking [H-3]ACh release. KA-stimulated [H-3]ACh r elease was largely blocked by NMDA antagonists, suggesting mediation throug h activation of NMDA receptors, probably secondary to KA-induced glutamate release. A selective group II metabotropic receptor agonist inhibited NMDA- stimulated [C-14]GABA and [H-3]ACh release. On the other hand, NMDA-stimula ted [C-14]GABA release was potentiated by activation of group I metabotropi c receptors. Thus, in addition to the differential modulation by D-1- and D -2-like receptors, the release of striatal neurotransmitters by NMDA recept or activation depends on the extent to which the other glutamate receptors, both ionotropic and metabotropic, are activated. (C) 1999 Published by Els evier Science B.V. All rights reserved.