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Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice

The Pharmacogenomics Journal volume 12, pages 147–155 (2012)Cite this article

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Abstract

Pharmacogenomics is yet to fulfill its promise of manifestly altering clinical medicine. As one example, a predictive test for tardive dyskinesia (TD) (an adverse drug reaction consequent to antipsychotic exposure) could greatly improve the clinical treatment of schizophrenia but human studies are equivocal. A complementary approach is the mouse-then-human design in which a valid mouse model is used to identify susceptibility loci, which are subsequently tested in human samples. We used inbred mouse strains from the Mouse Phenome Project to estimate the heritability of haloperidol-induced activity and orofacial phenotypes. In all, 159 mice from 27 inbred strains were chronically treated with haloperidol (3 mg kg−1 per day via subdermal slow-release pellets) and monitored for the development of vacuous chewing movements (VCMs; the mouse analog of TD) and other movement phenotypes derived from open-field activity and the inclined screen test. The test battery was assessed at 0, 30, 60, 90 and 120 days in relation to haloperidol exposure. As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS). Unexpectedly, factor analysis demonstrated that these measures were imprecise assessments of a latent construct rather than discrete constructs. The heritability of a composite phenotype was ∼0.9 after incorporation of the longitudinal nature of the design. Murine VCMs are a face valid animal model of antipsychotic-induced TD, and heritability estimates from this study support the feasibility of mapping of susceptibility loci for VCMs.

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Acknowledgements

We thank Drs Andrea Pinheiro and Randy Nonneman for helpful discussions. The mice used in this study were acquired as part of the Mouse Phenome Project, an ongoing international collaborative effort headquartered at The Jackson Laboratory (Bar Harbor, ME, USA). This work was supported by the Pharmacogenetics Research Network (U01 GM63340, PI Dr McLeod), a NIMH/NHGRI Center of Excellence for Genome Sciences grant (P50 MH90338, PIs Drs Fernando Pardo-Manuel de Villena and Sullivan) and the Mouse Behavioral Phenotyping Laboratory (NICHD P30 HD03110, PI Dr Joseph Piven). Dr Sullivan was supported by MH080403, MH077139 and MH074027.

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Authors and Affiliations

  1. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    J J Crowley, A L Pratt, C R Quackenbush & P F Sullivan

  2. Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC, USA

    J J Crowley, K C Wilhelmsen & H L McLeod

  3. Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth University, Richmond, VA, USA

    D E Adkins & E J van den Oord

  4. Neurodevelopmental Disorders Research Center, University of North Carolina, Chapel Hill, NC, USA

    S S Moy

  5. Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, USA

    T B Cooper

  6. The Jackson Laboratory, Bar Harbor, ME, USA

    M A Bogue

  7. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    P F Sullivan

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  1. J J Crowley
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Correspondence to J J Crowley.

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Competing interests

Dr Sullivan reports receiving unrestricted research funding from Eli Lilly for genetic research in schizophrenia. The other authors declare no conflict of interest.

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On-line resources

Phenotypic data from this project will be available via the Mouse Phenome Database (MPD; http://www.jax.org/phenome) on 1 April 2011.

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

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Crowley, J., Adkins, D., Pratt, A. et al. Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice. Pharmacogenomics J 12, 147–155 (2012). https://doi.org/10.1038/tpj.2010.82

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