Acute N-methyl-d-aspartate receptor hypofunction induced by MK801 evokes sex-specific changes in behaviors observed in open-field testing in adult male and proestrus female rats

• Published in: Neuroscience Vol. 228; pp. 200 - 214
• Main Authors: Feinstein, I., Kritzer, M.F.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 03.01.2013; Elsevier
• Subjects: Adult and adolescent clinical studies; Animals; Biological and medical sciences; clozapine; dizocilpine; Dizocilpine Maleate - pharmacology; Female; Grooming - drug effects; Grooming - physiology; haloperidol; Male; Medical sciences; Motor Activity - drug effects; Motor Activity - physiology; negative symptoms; Neurology; Neuropharmacology; Pharmacology. Drug treatments; positive symptoms; Proestrus - drug effects; Proestrus - physiology; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - physiology; Schizophrenia; Sex Characteristics; Stereotyped Behavior - drug effects; Stereotyped Behavior - physiology; Time Factors; CLZ; HDL; haloperidol; positive symptoms; ANOVA; negative symptoms; PLSD; NMDAR; clozapine; schizophrenia; dizocilpine; DIC; differential interference contrast; N-methyl- d-aspartate receptor; protected least significant difference; analyses of variance; Rat; Neuroleptic; Psychotropic; Dizocilpine; Rodentia; Sex; Schizophrenia; Male; Glutamate receptor; Clozapine; Haloperidol; Open field behavior; Psychosis; Vertebrata; Mammalia; Animal; Female; Antagonist; NMDA receptor
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2012.10.026

► MK801 has sex-specific effects on seven open-field behaviors in rats. ► The sex-specific effects of MK801 parallel some sex differences in schizophrenia. ► Neuroleptics have similar effects on MK801-induced behaviors in male and female rats. ► NMDAR hypofunction models may be useful in studying sex differences in psychosis. Schizophrenia is a complex constellation of positive, negative and cognitive symptoms. Acute administration of the non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDAR) dizocilpine (MK801) in rats is one of few preclinical animal models of this disorder that has both face and/or construct validity for these multiple at-risk behavioral domains and predictive power for the efficacy of therapeutic drugs in treating them. This study asked whether and to what extent the rat NMDAR hypofunction model also embodies the sex differences that distinguish the symptoms of schizophrenia and their treatment. Thus, we compared the effects of acute MK801, with and without pretreatment with haloperidol or clozapine, on seven discrete spontaneous open-field activities in adult male and female rats. These analyses revealed that MK801 was more effective in stimulating ataxia and locomotion and inhibiting stationary behavior in females while more potently stimulating stereotypy and thigmotaxis and inhibiting rearing and grooming in males. Haloperidol and clozapine pretreatments had markedly different efficacies in terms of behaviors but strong similarities in their effectiveness in male and female subjects. These results bear intriguing relationships with the complex male/female differences that characterize the symptoms of schizophrenia and suggest possible applications for acute NMDAR hypofunction as a preclinical model for investigating the neurobiology that underlies them.