NMDA antagonists: lack of antipunishment effect in squirrel monkeys

Effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) and competitive antagonists 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) were studied in 6 squirrel monkeys trained under a multiple schedule of unpunished and punished lever pressing. PCP (0.03-0.3 mg/kg, IM) failed to produce increases in punished responding, even at doses that produced extreme response-rate decreases in nonpunishment components. Similarly, CPP (1-17 mg/kg) and NPC 12626 (3-30 mg/kg) did not produce increases in punished responding at any dose tested. Repeated administration of NPC 12626 (17 mg/kg) for 4 consecutive days did not result in increased rates of punished responding. The benzodiazepine anxiolytic midazolam (0.3 mg/kg) and, to a lesser extent, the barbiturate pentobarbital (5.6 mg/kg), produced increases in punished responding in the same subjects at doses that did not markedly affect unpunished responding. Coadministration of PCP (0.03 mg/kg) with doses of midazolam ranging from 0.03-3 mg/kg did not produce changes in the midazolam dose-response curve for either unpunished or punished responding. These results fail to support findings in rats that NMDA antagonists produce antipunishment effects similar to those of benzodiazepine anxiolytics.