PT  - JOURNAL ARTICLE
AU  - Witkin, J M
AU  - Brave, S
AU  - French, D
AU  - Geter-Douglass, B
TI  - 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.
DP  - 1995 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1267--1273
VI  - 275
IP  - 3
4099  - http://jpet.aspetjournals.org/content/275/3/1267.short
4100  - http://jpet.aspetjournals.org/content/275/3/1267.full
SO  - J Pharmacol Exp Ther1995 Dec 01; 275
AB  - The strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2-one], a low-efficacy partial agonist of the glycine site, was 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-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative 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 (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1, 2-cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did not substitute, this 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% dizoclipine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site.(ABSTRACT TRUNCATED AT 250 WORDS)