title: Antipsychotic-induced vacuous chewing movements and extrapyramidal side effects are highly heritable in mice.
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.
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA. crowley@unc.edu
authors.forename: J J
authors.initials: JJ
authors.lastname: Crowley
authors.forename: D E
authors.initials: DE
authors.lastname: Adkins
authors.forename: A L
authors.initials: AL
authors.lastname: Pratt
authors.forename: C R
authors.initials: CR
authors.lastname: Quackenbush
authors.forename: E J
authors.initials: EJ
authors.lastname: van den Oord
authors.forename: S S
authors.initials: SS
authors.lastname: Moy
authors.forename: K C
authors.initials: KC
authors.lastname: Wilhelmsen
authors.forename: T B
authors.initials: TB
authors.lastname: Cooper
authors.forename: M A
authors.initials: MA
authors.lastname: Bogue
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
authors.forename: P F
authors.initials: PF
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects*; D006220:Haloperidol / Q000009:adverse effects*; D008297:Male; D008409:Mastication / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains
chemical_list: D014150:Antipsychotic Agents; D006220:Haloperidol