Abstract

Several pharmacologically distinct sites are known to modulate the N-methyl-d-aspartate (NMDA) receptor/ion complex, including a site within the ion channel which binds uncompetitive antagonists like phencyclidine (PCP) or dizocilpine. Glycine acts as a co-agonist for activation of the NMDA receptor complex through a strychnine-insensitive receptor, which is a potential target for novel therapeutic agents (e.g., anticonvulsants, antidepressants). We evaluated the behavioral effects of glycine receptor ligands in rats trained to discriminate either dizocilpine or PCP from saline, to predict whether glycine receptor ligands might induce undesirable PCP-like subjective effects in humans. Dizocilpine ([+]-MK-801), (−)-MK-801 and PCP produced dose-dependent substitution in these rats with potencies in accord with NMDA receptor affinity. Pentobarbital and drugs acting at other sites of the NMDA receptor, including competitive antagonists (NPC 12626 and LY 274614) and the polyamine antagonist, ifenprodil, did not substitute for either dizocilpine or PCP. In contrast to the uncompetitive antagonists like PCP, none of the strychnine-insensitive glycine receptor ligands substituted. Neither the full agonist, glycine; the partial agonists, 1-amino-1-cyclopropanecarboxylic acid,d-cycloserine or (+)-3-amino-1-hydroxypyrrolid-2-one; nor the antagonists, 7-chloro and 5,7-dichlorokynurenic acid, mimicked the discriminative stimulus effects of dizocilpine or PCP. Further, co-administration of 1-amino-1-cyclopropanecarboxylic acid did not significantly enhance the discriminative stimulus effects of dizocilpine. Intracerebroventricular administration ofd-serine, a selective agonist of the strychnine-insensitive glycine receptor, neither mimicked nor blocked the discriminative stimulus effects of PCP. These data suggest that functional antagonists of the strychnine-insensitive glycine receptor may be devoid of the subjective side effects characteristic of NMDA channel ligands.