MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys.

MK-801, a proposed NMDA antagonist, produced behavioral effects in pigeons, rats, and rhesus monkeys that closely resembled those of phencyclidine (PCP), including catalepsy, discriminative stimulus effects, locomotion, sniffing, positive reinforcing effects, and anesthesia without eye closure or respiratory depression. MK-801 was 2 to 10 times more potent than PCP depending on the species and effect measured. These findings support the hypothesis that certain PCP-like behavioral effects may result from reduced neurotransmission at NMDA-preferring receptors. The behavioral similarities suggest that clinical trials of MK-801 should evaluate PCP-like activity.

Study at a glance

Abstract

The behavioral effects of MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e], a proposed noncompetitive N-methyl-D-aspartate (NMDA) 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.