EFFECTS OF STRYCHNINE-INSENSITIVE GLYCINE RECEPTOR LIGANDS IN RATS DISCRIMINATING DIZOCILPINE OR PHENCYCLIDINE FROM SALINE

Several pharmacologically distinct sites are known to modulate the N-m ethyl-D-aspartate (NMDA) receptor/ion complex, including a site within the ion channel which binds uncompetitive antagonists like phencyclid ine (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 far novel therapeutic agents (e.g., anti convulsants, antidepressants). We evaluated the behavioral effects of glycine receptor ligands in rats trained to discriminate either dizoci lpine or PCP from saline, to predict whether glycine receptor ligands might induce undesirable PCP-like subjective effects in humans. Dizoci lpine ([+]-MK-801), (-)-MK-801 and PCP produced dose-dependent substit ution in these rats with potencies in accord with NMDA receptor affini ty. 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 nat substitute for either dizoci lpine or PCP. In contrast to the uncompetitive antagonists like PCP, n one of the strychnine-insensitive glycine receptor ligands substituted . Neither the full agonist, glycine; the partial agonists, 1-amino-1-c yclopropanecarboxylic acid, D-cycloserine or (+)-3-amino-1-hydroxypyrr olid-2-one; nor the antagonists, 7-chloro and 5,7-dichlorokynurenic ac id, 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 d izocilpine. Intracerebroventricular administration of D-serine, a sele ctive 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-insensitiv e glycine receptor may be devoid of the subjective side effects charac teristic of NMDA channel ligands.