gray-clozapinereverses-2008.pdf (234.54 kB)
Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-d-aspartic acid receptor up-regulation
journal contribution
posted on 2009-02-01, 00:00 authored by Laura GrayLaura Gray, M van den Buuse, E Scarr, B Dean, A J HannanAbnormalities 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.
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Journal
The international journal of neuropsychopharmacologyyVolume
12Pagination
45 - 60Publisher
Oxford University PressLocation
Oxford, Eng.Publisher DOI
ISSN
1461-1457eISSN
1469-5111Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2009, Oxford University PressUsage metrics
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Science & TechnologyLife Sciences & BiomedicineClinical NeurologyNeurosciencesPharmacology & PharmacyPsychiatryNeurosciences & NeurologyAntipsychoticbehaviourmGluR5NMDAINDUCED COGNITIVE DEFICITSLONG-TERM POTENTIATIONPREPULSE INHIBITION DEFICITMGLUR5 ANTAGONISTPREFRONTAL CORTEXIN-VIVOANTIPSYCHOTIC-DRUGSLOCOMOTOR-ACTIVITYGENE-EXPRESSIONNMDA RECEPTORS
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