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 fi ve responses show differing sensitivities to NMDA and also to a variet y of competitive antagonists, NMDA channel blockers, glycine antagonis ts and polyamine site antagonists. 3. Inhibitory activity profiles for 20 different antagonists are presented. All compounds tested showed s ome degree of selectivity with regard to the different responses and e ach response showed particular characteristics that suggested mediatio n by a particular native NMDA receptor subtype. 4. Receptors controlli ng dopamine, GABA and noradrenaline release were generally more sensit ive to most antagonists compared to those controlling acetylcholine an d spermidine release. 5. Receptors controlling spermidine release were furthermore insensitive to magnesium, argiotoxin, ifenprodil and elip rodil and displayed low sensitivity to memantine, dextrorphan and dext romethorphan. 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 a ntagonist 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 wi de diversity of native NMDA receptors with different properties and an unexpectedly rich pharmacopeia of subtype selective antagonists of na tive NMDA receptors. 8. Matching subtype selectivity to particular beh avioural effects may be possible and the design of subtype selective N MDA antagonists for particular clinical applications while avoiding si de effect generation seems to be feasible.