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

• Published in: The pharmacogenomics journal Vol. 12; no. 2; pp. 147 - 155
• Main Authors: Crowley, J J, Adkins, D E, Pratt, A L, Quackenbush, C R, van den Oord, E J, Moy, S S, Wilhelmsen, K C, Cooper, T B, Bogue, M A, McLeod, H L, Sullivan, P F
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.04.2012
• Subjects: Animal models; Animals; Antipsychotic Agents - adverse effects; Antipsychotic drugs; Antipsychotics; Chewing; Complications and side effects; Disease susceptibility; Extrapyramidal system; Factor analysis; Feasibility studies; Gene mapping; Haloperidol; Haloperidol - adverse effects; Health aspects; Heritability; Inbreeding; Male; Mastication; Mastication - drug effects; Mastication - genetics; Medicin och hälsovetenskap; Mental disorders; Mice; Mice, Inbred Strains; Movement disorders; Open-field behavior; Pharmacogenomics; Phenotypes; Psychotropic drugs; Schizophrenia; Tardive dyskinesia; United States; Sweden
• ISSN: 1470-269X; 1473-1150; 1473-1150
• DOI: 10.1038/tpj.2010.82

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.