Characterization of MK-801-Induced Behavior as a Putative Rat Model of Psychosis1
- Peter Andiné1,2,
- Nina Widermark2,
- Rolf Axelsson3,
- Gösta Nyberg3,
- Ulla Olofsson3,
- Erik Mårtensson3 and
- Mats Sandberg2
- 1Institute of Clinical Neuroscience, Department of Psychiatry, Sahlgrenska University Hospital (P.A.); and 2Institute of Anatomy and Cell Biology (P.A., N.W., M.S.) and 3Psychiatric Research Unit, Sahlgrenska University Hospital (R.A., G.N., U.O., E.M.), Göteborg University, Göteborg, Sweden
Abstract
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 anN-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.
Footnotes
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Send reprint requests to: Dr. Peter Andiné, Institute of Clinical Neuroscience, Department of Psychiatry, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail:peter.andine{at}sahlgrenska.se
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↵1 This work was supported by the H. Lundbeck Psychosis Foundation, the Tore Nilsson Foundation, the Lars Hierta Foundation, the Medical Faculty of Göteborg University, the Åke Wiberg Foundation, the Swedish Society of Medicine, the Royal Society of Arts and Sciences in Göteborg, the Åhlén Foundation, the Swedish Care and Treatment of Psychoses Committee, the Adlerbertska Foundation, the Sahlgrenska University Hospital Foundations, and the Swedish Medical Research Council (11643 and 11840).
- Abbreviations:
- EAA
- excitatory amino acid
- NMDA
- N-methyl-d-aspartate
- AMPA
- α-amino-3-hydroxy-5-methyl-isoxazole-4-proprionic acid
- MK-801
- (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (dizocilpine maleate)
- acivicin
- (αS, 5S)-α-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125)
- GYKI
- 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466 hydrochloride)
- NBQX
- 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium
- DIAZ
- diazepam
- DCS
- d-cycloserine
- HA-966
- R(+)-3-amino-1-hydroxy-2-pyrrolidinone
- IFEN
- α-(4-hydroxyphenyl)-β-(4-benzylpiperidin-1-yl) β-methylethanol tartrate (ifenprodil tartrate)
- RISP
- risperidone
- PERPH
- perphenazine
- CLOZ
- clozapine
- CHLOR
- chlorpromazine
- HAL
- haloperidol
- REM
- remoxipride
- NECA
- 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-l-ribofuranuronamide (5′-N-ethylcarboxamido adenosine)
- THEO
- theophylline
- R-PIA
- R(−)N6-(2-phenylisopropyl)adenosine
- DPCPX
- 8-cyclopentyl-1,3-dipropylxanthine
- CHA
- N6-cyclohexyladenosine
- DMPX
- 3,7-dimethyl-1-propargylxanthine
- CGS-21680
- 2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamido adenosine hydrochloride
- cyclothiazide
- 3-bicyclo[2.2.1]hept-5-en-2-yl-6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
- PC
- parietal cortex
- FC
- frontal cortex
- HY
- hypothalamus
- SP
- striatum posterior
- SA
- striatum anterior
- HI
- hippocampus
- γ-GT
- γ-glutamyltransferase
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- Received January 22, 1999.
- Accepted April 11, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
