Striatal NMDA receptor subtypes: the pharmacology of N-methyl- d-aspartate-evoked dopamine, γ-aminobutyric acid, acetylcholine and spermidine release

We have examined the inhibitory potencies of MK 801, memantine, dextromethorphan, Mg 2+ and of strychnine-insensitive glycine site antagonists on the N-methyl- d-aspartate (NMDA)-evoked (300 μM) release of [ 14C]acetylcholine and [ 3H]spermidine or [ 14C]γ-aminobutyric acid [ 14C]GABa and [ 3H]dopamine from rat straiatal slices. MK 801, dextromethorphan and all glycine antagonists examined (7-chlorokynurenate, L-689,560 ((±)- trans-2-carboxy-5,7-dichlorotetrahydroquinoline-4-phenylurea), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dichloroquinoxaline-2,3-dione (DNQX), and (+)-HA966 ((3-amino-1-hydroxypyrrolidin-2-one) more potently inhibited NMDA-evoked dopamine and GABA release than acetylcholine and spermidine release by a factor of 3–21. MgCl 2, which does not inhibit NMDA-evoked spermidine release, and memantine which only weakly antagonised NMDA-evoked spermidine release, inhibited NMDA-evoked dopamine, acetylcholine and GABA release with similar potencies. No pharmacological 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 receptor subtypes in the striatum and suggest a third native subtype with a distinct pharmacology that regulates striatal dopamine and GABA release.