THE DISCRIMINATIVE STIMULUS EFFECTS OF MK-801 IN PIGEONS

The discriminative stimulus effects of MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo (a,d) cyclohepten-5,10-imine], a proposed noncompetitive N-methyl-D-aspartate (NMDA) antagonist, were studied in pigeons discriminating MK-801 from saline, responding being maintained by food. Compounds with noncompetitive NMDA antagonist effects in other preparations (PCP [0.18-5.6 mg/kg], dextrorphan [1-32 mg/kg], ketamine [1-32-mg/kg] and dexoxadrol [1-10 mg/kg]) produced MK-801-appropriate responding dosedependently. The potentcy order for this effect, and for response rate decreasing effects, closely mirrored the potency order for these compounds in causing catalepsy, an effect believed to be mediated by antagonism at the NMDA receptor complex. NMDA (0.32-5.6 mg/kg), morphine (1-10 mg/kg) and pentobarbital (1-17.8 mg/kg) produced almost no MK-801-appropriate responding. There were no consistent potency differences among the (+)-isomer (1-32 mg/kg), the (-)-isomer (1-17.8 mg/kg) and the racemate (1-17.8 mg/kg) of SKF 10,047 in producing MK-801-appropriate responding. The competitive NMDA antagonist CGS 19755 (1-10 mg/kg) produced partial MK-801-appropriate responding (maximum value = 77.8%) up to 8h after administration. The homogeneity of the discriminative stimulus effects among compounds with noncompetitive NMDA antagonist effects in vitro, as well as the partial substitution for MK-801 by CGS 19755, suggest that the MK-801 discriminative stimulus in pigeons is due to noncompetitive NMDA antagonism.