STRIATAL NMDA RECEPTOR SUBTYPES - THE PHARMACOLOGY OF N-METHYL-D-ASPARTATE-EVOKED DOPAMINE, GAMMA-AMINOBUTYRIC-ACID, ACETYLCHOLINE AND SPERMIDINE RELEASE

We have examined the inhibitory potencies of MK 801, memantine, dextro methorphan, Mg2+ and of strychnine-insensitive glycine site antagonist s on the N-methyl-D-aspartate (NMDA)-evoked (300 mu M) release of [C-1 4]acetylcholine and [H-3]spermidine or [C-14]gamma-aminobutyric acid [ C-14]GABA and [H-3]dopamine from rat striatal slices. MK 801, dextrome thorphan and all glycine antagonists examined (7-chlorokynurenate, L-6 89,560 2-carboxy-5,7-dichlorotetrahydroquinoline-4-phenyl urea), 6-cya no-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dichloroquinoxaline-2,3-di one (DNQX), and (+)-HA966 ((3-amino-1-hydroxypyrrolidin-2-one) more po tently inhibited NMDA-evoked dopamine and GABA release than acetylchol ine and spermidine release by a factor of 3-21. MgCl2, which does not inhibit NMDA-evoked spermidine release, and memantine which only weakl y antagonised NMDA-evoked spermidine release, inhibited NMDA-evoked do pamine, acetylcholine and GABA release with similar potencies. No phar macological differences were observed between NMDA-evoked dopamine and GABA release. These findings extend those suggesting that NMDA-evoked acetylcholine and spermidine release are mediated by different NMDA r eceptor subtypes in the striatum and suggest a third native subtype wi th a distinct pharmacology that regulates striatal dopamine and GABA r elease.