SENSITIVE AND RAPID BEHAVIORAL DIFFERENTIATION OF N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS

Behavioral effects of PCP-type noncompetitive antagonists of N-methyl- D-aspartate (NMDA) receptors overlap with those of a host of other cen trally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were use d to differentiate PCP-type noncompetitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (-)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose -related increases in locomotor activity and the percentage of mice fa lling off an inverted, elevated wire mesh screen. Both effects demonst rated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., an ticonvulsant). The potencies of these drugs for producing behavioral e ffects were positively correlated with affinities for PCP ([H-3]MK-801 ) but not sigma([H-3]SKF 10,047) receptors. Although muscarinic antago nists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), sigma receptor ligands (DTG, dextromethorpha n), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagon ists (haloperidol, SCH 39866), and some depressant compounds (morphine , diazepam) increased failures on the screen test but decreased locomo tor activity. Ligands of the polyamine regulatory site of the NMDA rec eptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQ X decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokyn urenic acid) did not affect performance on either test. Psychomotor st imulants (cocaine and methamphetamine) stimulated locomotor activity w ithout affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the pr esent procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists.