Characterization of MK-801-induced behavior as a putative rat model of psychosis.
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.
Andiné
P
P
Institute of Clinical Neuroscience, Department of Psychiatry, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden. peter.andine@sahlgrenska.se
Widermark
N
N
Axelsson
R
R
Nyberg
G
G
Olofsson
U
U
Mårtensson
E
E
Sandberg
M
M
D000375:Aging / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011605:Psychoses, Substance-Induced / Q000209:etiology* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000502:physiology; D012727:Sex Characteristics; D013239:Stereotyped Behavior / Q000187:drug effects*; D019956:Stereotypic Movement Disorder / Q000139:chemically induced
D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D007555:Isoxazoles; D018079:Receptors, GABA; D016291:Dizocilpine Maleate; C006303:acivicin