Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-D-aspartic acid receptor up-regulation.
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.
Gray
Laura
L
Howard Florey Institute, University of Melbourne, Victoria, Australia. laura.gray@gms.edu.sg
van den Buuse
Maarten
M
Scarr
Elizabeth
E
Dean
Brian
B
Hannan
Anthony J
AJ
D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000378:metabolism; D003024:Clozapine / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D005106:Exploratory Behavior / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000378:metabolism; D011869:Radioligand Assay; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics*; D012565:Schizophrenic Psychology; D012702:Serotonin Antagonists / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D014150:Antipsychotic Agents; D001549:Benzamides; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D018727:Muscarinic Antagonists; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D012702:Serotonin Antagonists; D003024:Clozapine; C030265:nemonapride