DIFFERENTIATION OF IN-VIVO EFFECTS OF AMPA AND NMDA RECEPTOR LIGANDS USING DRUG DISCRIMINATION METHODS AND CONVULSANT ANTICONVULSANT ACTIVITY/

The discriminative stimulus properties of the AMPA amino-3-(3-hydroxy- 5-methylisoxazol-4-yl)propionic acid) receptor agonist ATPA o-3-(3-hyd roxy-5-tert-butylisoxazol-4-yl)propionic acid) and NMDA (N-methyl-D-as partic acid) in rats have been characterized. It is suggested that the cues are mediated by separate mechanisms in the central nervous syste m. The ATPA cue is not mimicked by NMDA or an NMDA receptor agonist, a nd is inhibited by the AMPA receptor antagonist (R)-APPA amino-3-(3-hy droxy-5-phenylisoxazol-4-yl)propionic acid) but not the AMPA receptor antagonist ATOA carboxymethoxy-5-tert-butylisoxazol-4-yl)propionic aci d) or the NMDA receptor antagonist CPP ((RS)-3-(2-carboxypiperazin-4-y l)propyl)phosphonic acid). The ATPA cue is not mimicked by AMPA which is believed not to penetrate the blood-brain barrier. In contrast, ATP A does not generalize to the NMDA cue, which is mimicked by some NMDA receptor agonists (tetrazol-5-yl-gylcine and AMAA -2-amino-2-(3-hydrox y-5-methylisoxazol-4-yl)acetic acid)) and is inhibited by the NMDA rec eptor antagonist CPP. Highly potent convulsant activity was demonstrat ed in mice with all AMPA and NMDA receptor agonists after intracerebro ventricular (i.c.v.) injection, whereas weaker or no effects were foun d after subcutaneous (s.c.) or intravenous injection. Only (RS)-tetraz ol-5-yl-glycine had a potent effect after s.c. administration. I.c.v. ATOA and CPP inhibited convulsions induced by i.c.v. injection of AMPA or NMDA, while (R)-APPA was ineffective. These results indicate that there are differences in the structure-activity relations in the drug discrimination and convulsant/anticonvulsant models, even when effects after i.c.v. and s.c. injection are taken into consideration. The con vulsion models are rapid tests which can give an indication of central nervous system penetration, but are less pharmacologically specific w ith respect to differentiation between AMPA and NMDA ligands where cue models demonstrate clear differences in effects of ligands with selec tivity for receptor subtypes.