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Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice

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Abstract

Rationale

Schizophrenic patients show decreased measures of sensorimotor gating, such as prepulse inhibition of startle (PPI). In preclinical models, these measures may be used to predict antipsychotic activity. While current antipsychotic drugs act largely at dopamine receptors, the muscarinic acetylcholine receptors offer promising novel pharmacotherapy targets. Of these, the M5 receptor gene was recently implicated in susceptibility to schizophrenia. Due to the lack of selective ligands, muscarinic receptor knockout mice have been generated to elucidate the roles of the five receptor subtypes (M1–M5).

Objectives

Here, we used M5 receptor knockout (M5−/−) mice to investigate the involvement of M5 receptors in behavioral measures pertinent to schizophrenia. We tested the hypothesis that disruption of M5 receptors affected PPI or the effects of muscarinic or dopaminergic agents in PPI or psychomotor stimulation.

Materials and methods

We measured PPI in M5−/−, heterozygous and wild-type mice without drugs, and with clozapine (0.56–3.2 mg/kg) or haloperidol (0.32–3.2 mg/kg) alone, and as pretreatment to d-amphetamine. In addition, we evaluated locomotor stimulation by the muscarinic antagonist trihexyphenidyl (0.56–56 mg/kg) and by cocaine (3.2–56 mg/kg).

Results

The M5−/− mice showed decreased PPI relative to wild-type mice, and clozapine appeared to reduce this difference, while haloperidol increased PPI regardless of genotype. The M5−/− mice also showed more locomotor stimulation by trihexyphenidyl than wild-type mice, while cocaine had similar effects between genotypes.

Conclusions

These data suggest that disruption of the M5 receptor gene affected sensorimotor gating mechanisms, increased sensitivity to clozapine and to the psychostimulant effects of muscarinic antagonists without modifying the effect of dopaminergic drugs.

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Acknowledgements

This research was supported by NIH/NIDA grants P01-DA14528, T32-DA07252, the Lundbeck Foundation and the Zaffaroni Foundation. All procedures were carried out in accordance with the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (National Research Council 2003).

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Authors and Affiliations

  1. Alcohol and Drug Abuse Research Center, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont, MA, 02478, USA

    Morgane Thomsen & S. Barak Caine

  2. Laboratory of Neuropsychiatry, Rigshospitalet University Hospital, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark

    Gitta Wörtwein, Anders Fink-Jensen & David P. D. Woldbye

  3. Department of Pharmacology, University of Copenhagen, 9 Blegdamsvej, DK-2100, Copenhagen, Denmark

    Gitta Wörtwein, Anders Fink-Jensen & David P. D. Woldbye

  4. Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Jürgen Wess

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  1. Morgane Thomsen
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Correspondence to Morgane Thomsen.

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Thomsen, M., Wörtwein, G., Fink-Jensen, A. et al. Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice. Psychopharmacology 192, 97–110 (2007). https://doi.org/10.1007/s00213-006-0682-y

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