DISCRIMINATIVE STIMULUS EFFECTS OF R-(-3-AMINO-1-HYDROXYPYRROLID-2-ONE, [(+)-HA-966], A PARTIAL AGONIST OF THE STRYCHNINE-INSENSITIVE MODULATORY SITE OF THE N-METHYL-D-ASPARTATE RECEPTOR())

The strychnine-insensitive glycine site on the N-methyl-D-aspartate (N MDA) receptor complex is a target for development of a host of therape utic agents including anxiolytics, antidepressants, antiepileptics, an ti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-5-amino-1-hydroxy pyrrolid-2-one], a low-efficacy partial agonist of the glycine site, w as explored. Male, Swiss-Webster mice were trained to discriminate (+) -HA-966 (170 mg/kg i.p.) from saline in a T-maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cycl opropanecarboxilic acid and D-cycloserine, fully substituted for the d iscriminative stimulus effects of (+)-HA-966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7-chlorkynurenic acid, did not substitute for (+)-HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizoc ilpine) or low affinity (ibogaine) ion-channel blocker, the competitiv e antagonist, NPC 17742 -2-amino-4,5-(1,2-cyclohexyl)-7-phosphonohepta noic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did riot substitute, t his compound fully blocked the discriminative stimulus effects of (+)- HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizocilpine-appropriate responses. These data suggest that the discri minative stimulus effects of (+)-HA-966 are based upon its partial ago nist actions at the strychnine-insensitive glycine site. Furthermore, the lack of substitution of compounds with phencyclidine-like effects (dizocilpine, ibogaine and NPC 17742) or sedative properties (NPC 1774 2 and (-)-HA-966) suggests that these side-effects may not be part of the subjective effect profile of glycine partial agonists.