The pharmacology of native N-methyl-D-aspartate receptor subtypes: different receptors control the release of different striatal and spinal transmitters.

1. N-methyl-D-aspartate (NMDA) increases the release of radiolabelled dopamine, GABA, acetylcholine and spermidine from rat striatal slices and of noradrenaline from the dorsal cervical spinal cord. 2. These five responses show differing sensitivities to NMDA and also to a variety of competitive antagonists, NMDA channel blockers, glycine antagonists and polyamine site antagonists. 3. Inhibitory activity profiles for 20 different antagonists are presented. All compounds tested showed some degree of selectivity with regard to the different responses and each response showed particular characteristics that suggested mediation by a particular native NMDA receptor subtype. 4. Receptors controlling dopamine, GABA and noradrenaline release were generally more sensitive to most antagonists compared to those controlling acetylcholine and spermidine release. 5. Receptors controlling spermidine release were furthermore insensitive to magnesium, argiotoxin, ifenprodil and eliprodil and displayed low sensitivity to memantine, dextrorphan and dextromethorphan. 6. Receptors controlling noradrenaline release could be further discriminated from those controlling dopamine and GABA release by very high sensitivity to magnesium and MK-801 and to the glycine antagonist L-689,560 but not to other glycine antagonists (CNQX, DNQX, 7-Chlorokynurenate, HA-966). 7. Many other individual drug or receptor differences were noted. The different profiles observed suggest a wide diversity of native NMDA receptors with different properties and an unexpectedly rich pharmacopeia of subtype selective antagonists of native NMDA receptors. 8. Matching subtype selectivity to particular behavioural effects may be possible and the design of subtype selective NMDA antagonists for particular clinical applications while avoiding side effect generation seems to be feasible.