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Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice

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Abstract

Rationale

Prepulse inhibition of the startle response (PPI), a model of sensorimotor gating, is deficient in persons with schizophrenia. In rodents, the reversal of induced deficits in PPI demonstrates predictive validity for identifying antipsychotic treatments. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in schizophrenia, in part because mGluR5 knockout (KO) mice exhibit PPI deficits.

Objective

We examined whether mGluR5 KO mice might serve as a novel model for detecting antipsychotic treatments.

Methods

Using C57BL/6J or 129SvPasIco mice, we first determined doses of the typical antipsychotic raclopride or the atypical antipsychotic clozapine that were effective in blocking the PPI-disruptive effects of amphetamine or ketamine, respectively. We then examined the effects of these doses on the deficit in PPI in mGluR5 KO mice.

Results

Administration of raclopride or clozapine reversed either an amphetamine or a ketamine-induced PPI deficit, as had the novel mood stabilizer lamotrigine in previous studies. In contrast, the PPI deficit of the mGluR5 KO mice was not altered by administration of raclopride, clozapine, or lamotrigine. The serotonin2A antagonist M100,907 was also ineffective in reversing the mGluR5 KO deficit in PPI.

Conclusions

Most of the compounds examined ameliorated at least a subset of pharmacologically induced PPI deficits. That none of the antipsychotic treatments attenuated the PPI deficit in the mGluR5 KO mice indicates that this model is not predictive of known treatments for schizophrenia, but does not preclude a role for the mGluR5 receptor in schizophrenia or other psychiatric disorders.

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Acknowledgements

The authors wish to thank Dr. John Roder for creation of the mGluR5 KO mice and for making them available for research. S.A.B. was supported by a Training Grant from the National Institute of Mental Health (NIMH; F31MH12961). This work was supported by the Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center and by grants from the National Institute on Drug Abuse (R01DA02925) and NIMH (R37MH42228). M.A.G. holds an equity interest in San Diego Instruments.

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Authors and Affiliations

  1. Departments of Psychiatry and Neurosciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA

    S. A. Brody & M. A. Geyer

  2. GlaxoWellcome Experimental Research, IBCM, University of Lausanne, Lausanne, 1005, Switzerland, Switzerland

    F. Conquet

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  1. S. A. Brody
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  2. F. Conquet
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  3. M. A. Geyer
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Correspondence to M. A. Geyer.

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Brody, S.A., Conquet, F. & Geyer, M.A. Effect of antipsychotic treatment on the prepulse inhibition deficit of mGluR5 knockout mice. Psychopharmacology 172, 187–195 (2004). https://doi.org/10.1007/s00213-003-1635-3

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  • DOI: https://doi.org/10.1007/s00213-003-1635-3

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