EFFECTS OF SITE-SELECTIVE NMDA RECEPTOR ANTAGONISTS IN AN ELEVATED PLUS-MAZE MODEL OF ANXIETY IN MICE

NMDA receptor antagonists have been shown to be anxiolytic in animal m odels of anxiety, although they have not been tested extensively. Thes e compounds bind to several specific sites within the NMDA-receptor co mplex, including the NMDA site itself, the phencyclidine site, and the strychnine-insensitive glycine site. The purpose of the present study was to examine potential anxiolytic effects of site-selective NMDA re ceptor antagonists in the elevated plus-maze. Drug-naive albino mice w ere placed in the center of an elevated maze shaped like a plus sign. Two opposing arms were enclosed by high walls; the crossing arms were open. Following injection with drug or vehicle, the number of entries and time spent in each type of arm were measured during 5-min tests. A nalysis of results showed that the benzodiazepine, diazepam, and the c ompetitive NMDA receptor antagonist, NPC 17742 (2R,4R,5S 2-amino-4,5-( 1,2-cyclohexyl)-7-phosphono acid), increased number of open arm entrie s and open arm time. N-Nitro-L-arginine methyl ester, a nitric oxide s ynthase inhibitor which may interfere with the transduction of NMDA re ceptor activation, also increased open arm entries and time; however, the magnitude of these increases was small. The phencyclidine-site NMD A receptor antagonist, phencyclidine, increased open arm entries, but failed to significantly increase open arm time. ACEA 1021 ro-6,7-dichl oro-1,4-dihydro-2,3-quinoxalinedione), a putative glycine-site antagon ist, had significant effects only on open arm entries at the highest d ose tested. These results suggest that NMDA receptor antagonists show promise as potential anxiolytic agents, but that differences among ant agonists acting at different cellular sites may be expected.