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Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation

Gray, Laura, van den Buuse, Maarten, Scarr, Elizabeth, Dean, Brian and Hannan, Anothony J. 2009, Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation, The international journal of neuropsychopharmacology, vol. 12, pp. 45-60, doi: 10.1017/S1461145708009085.

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Title Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation
Author(s) Gray, Laura
van den Buuse, Maarten
Scarr, Elizabeth
Dean, Brian
Hannan, Anothony J.
Journal name The international journal of neuropsychopharmacology
Volume number 12
Start page 45
End page 60
Total pages 16
Publisher Oxford University Press
Place of publication Oxford, Eng.
Publication date 2009-02
ISSN 1461-1457
1469-5111
Summary Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.
Key words
Language eng
DOI 10.1017/S1461145708009085
Field of Research 111699 Medical Physiology not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2009, Oxford University Press
Persistent URL http://hdl.handle.net/10536/DRO/DU:30075521

Document type: Journal Article
Collection: School of Medicine
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