MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys.
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.
Koek
W
W
Department of Pharmacology, University of Michigan, Ann Arbor.
Woods
J H
JH
Winger
G D
GD
D000758:Anesthesia; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D010856:Columbidae; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D016291:Dizocilpine Maleate; D007649:Ketamine / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D016202:N-Methylaspartate; D010622:Phencyclidine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012646:Self Administration; D009435:Synaptic Transmission / Q000187:drug effects*
D000927:Anticonvulsants; D003986:Dibenzocycloheptenes; D001224:Aspartic Acid; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D010622:Phencyclidine