Maarten van den Buuse1,2,3,4, Jac Kee Low5,6, Perrin Kwek5, Sally Martin5, Andrea Gogos5,7. 1. Mental Health Research Institute, Parkville, VIC, Australia. m.vandenbuuse@latrobe.edu.au. 2. Department of Pharmacology, University of Melbourne, Melbourne, VIC, Australia. m.vandenbuuse@latrobe.edu.au. 3. The College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia. m.vandenbuuse@latrobe.edu.au. 4. School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia. m.vandenbuuse@latrobe.edu.au. 5. Mental Health Research Institute, Parkville, VIC, Australia. 6. School of Nursing and Midwifery, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, 3800, Australia. 7. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
Abstract
RATIONALE: Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. OBJECTIVES: This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. RESULTS: The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [3H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. CONCLUSIONS: These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.
RATIONALE: Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness. OBJECTIVES: This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice. RESULTS: The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [3H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX. CONCLUSIONS: These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.
Entities:
Keywords:
NMDA receptor; Schizophrenia; Sex hormones; Testosterone
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