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

Laura Gray*, Maarten Van Den Buuse, Elizabeth Scarr, Brian Dean, Anthony J. Hannan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

Abstract

Abstract 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.

Original languageEnglish
Pages (from-to)45-60
Number of pages16
JournalInternational Journal of Neuropsychopharmacology
Volume12
Issue number1
DOIs
Publication statusPublished - Feb 2009
Externally publishedYes

Keywords

  • Antipsychotic
  • Behaviour
  • MGluR5
  • NMDA

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