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Vol. 290, Issue 3, 1393-1408, September 1999

Characterization of MK-801-Induced Behavior as a Putative Rat Model of Psychosis1

Peter Andiné , Nina Widermark, Rolf Axelsson, Gösta Nyberg, Ulla Olofsson, Erik Mårtensson and Mats Sandberg

Institute of Clinical Neuroscience, Department of Psychiatry, Sahlgrenska University Hospital (P.A.); and Institute of Anatomy and Cell Biology (P.A., N.W., M.S.) and Psychiatric Research Unit, Sahlgrenska University Hospital (R.A., G.N., U.O., E.M.), Göteborg University, Göteborg, Sweden

The objective of this study was to characterize the behavior induced by the N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine maleate) in rats as a model of psychosis. The temporal profile, dose dependence, age, and sex differences of the behavior are described. A gas chromatographic method for the analysis of MK-801 in plasma and brain was developed. Female rats showed 4 to 10 times more MK-801-induced behavior and displayed around 25 times higher serum and brain concentrations of MK-801 than male rats. Twenty-one neuroactive compounds, including a number of excitatory amino acid-active substances, were tested for the effect on MK-801-induced behavior. Neuroleptics blocked MK-801-induced behavior in a dose-dependent manner that correlated to their antipsychotic potency in humans. Adenosine receptor agonists and an N-methyl-D-aspartate receptor-associated glycine site antagonist showed putative antipsychotic effects. In conclusion, MK-801-induced behavior represents a rat excitatory amino acid hypofunction model of psychosis that appears to be of clinical relevance and may be of value in the search for new antipsychotic agents.

0022-3565/99/2903-1393$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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