MK-801, A PROPOSED NONCOMPETITIVE ANTAGONIST OF EXCITATORY AMINO-ACID NEUROTRANSMISSION, PRODUCES PHENCYCLIDINE-LIKE BEHAVIORAL-EFFECTS IN PIGEONS, RATS AND RHESUS-MONKEYS

Abstract

The behavioral effects of MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine], a proposed noncompetitive N-methyl-D-aspartate (NDMA) antagonist, were compared to those of phencyclidine(PCP). In pigeons, MK-801 produced PCP-like catalepsy (i.e., loss of righting without eye closure and without muscle relaxation) and PCP-like discriminative stimulus effects. In rats, MK-801 produced PCP-like behavior (i.e., locomotion, sniffing, swaying and falling). In rhesus monkeys, like PCP, MK-801 produced 1) ketamine-like discriminative stimulus effects, 2) positive reinforcing effects and 3) ketamine-like anesthetic effects (i.e., anesthesia without eye closure and without respiratory depression, but with profuse salivation and with some muscle relaxation). Thus, MK-801 produced PCP-like behavioral effects in each species and with each procedure. MK-801 was 2 to 10 times more potent than PCP, depending on the effect measured and the species tested. Because MK-801 has been shown to have NMDA-antagonist properties, the findings of this study offer further support for the hypothesis that certain behavioral effects of PCP-like drugs may result from a reduction of neurotransmission at excitatory synapses utilizing NMDA-preferring receptors. The behavioral similarities between MK-801 and PCP make it relevant to evaluate PCP-like activity in clinical trials of MK-801.