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.
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Acknowledgements
These studies were supported by a project grant from the National Health and Medical Research Council (NHMRC) of Australia and Operational Infrastructure Support from the Victorian State Government. MvdB is a Senior Research Fellow and AG was supported by a postdoctoral training fellowship from the NHMRC. None of the funding bodies had any role in the study design, collection, analysis, and interpretation of the data, in the writing of the paper, or the decision to submit it for publication. The authors have no conflict of interest to report.
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All procedures were approved by the Florey Neuroscience Institutes Animal Experimentation Ethics Committee in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes set out by the National Health and Medical Research Council (NHMRC) of Australia.
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These studies were supported by a project grant from the National Health and Medical Research Council (NHMRC) of Australia and Operational Infrastructure Support from the Victorian State Government. MvdB is a Senior Research Fellow and AG was supported by a postdoctoral training fellowship from the NHMRC. The authors have no conflict of interest to report.
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van den Buuse, M., Low, J.K., Kwek, P. et al. Selective enhancement of NMDA receptor-mediated locomotor hyperactivity by male sex hormones in mice. Psychopharmacology 234, 2727–2735 (2017). https://doi.org/10.1007/s00213-017-4668-8
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DOI: https://doi.org/10.1007/s00213-017-4668-8