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

Crowley JJ, Adkins DE, Pratt AL, Quackenbush CR, van den Oord EJ, Moy SS, Wilhelmsen KC, Cooper TB, Bogue MA, McLeod HL, Sullivan PF - Pharmacogenomics J. (2010)

Bottom Line: As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA. crowley@unc.edu

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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Haloperidol plasma concentrations (in nM) per strain at four time pointsAll data points are shown for all strains with a non-linear smoothing function added.
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Figure 1: Haloperidol plasma concentrations (in nM) per strain at four time pointsAll data points are shown for all strains with a non-linear smoothing function added.

Mentions: Table S3 summarizes the number of mice used in this experiment, attrition over time, and the numbers of mice that achieved the minimum desired haloperidol concentrations at each time-point. The numbers of mice with steady-state plasma haloperidol concentrations ≥10 nM were 156/159 at 30 days, 151/158 at 60 days, 73/149 at 90 days, and 9/148 at 120 days, consistent with the function of the 60 day release tablets. Haloperidol concentrations in the three mice under the 10 nM threshold at 30 days were 9.4, 9.6, and 9.9 nM. Figure 1 shows full data for plasma haloperidol concentrations at 30, 60, 90, and 120 days. Although there is considerable variation across strains, haloperidol levels were almost always tightly clustered within each strain-time point with the possible exception of the heaviest strain (the mean baseline weight for NZL mice was four times the lightest strain). The medians (inter-quartile ranges) of the coefficients of variation for haloperidol concentrations across strains were 0.19 (0.15–0.25) at 30 days and 0.19 (0.13–0.25) at 60 days. These data are consistent with the pilot data in Table S2 and indicate that the delivery method almost always achieved our goal of exposure to sustained human-like haloperidol steady-state concentrations.


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

Crowley JJ, Adkins DE, Pratt AL, Quackenbush CR, van den Oord EJ, Moy SS, Wilhelmsen KC, Cooper TB, Bogue MA, McLeod HL, Sullivan PF - Pharmacogenomics J. (2010)

Haloperidol plasma concentrations (in nM) per strain at four time pointsAll data points are shown for all strains with a non-linear smoothing function added.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117923&req=5

Figure 1: Haloperidol plasma concentrations (in nM) per strain at four time pointsAll data points are shown for all strains with a non-linear smoothing function added.
Mentions: Table S3 summarizes the number of mice used in this experiment, attrition over time, and the numbers of mice that achieved the minimum desired haloperidol concentrations at each time-point. The numbers of mice with steady-state plasma haloperidol concentrations ≥10 nM were 156/159 at 30 days, 151/158 at 60 days, 73/149 at 90 days, and 9/148 at 120 days, consistent with the function of the 60 day release tablets. Haloperidol concentrations in the three mice under the 10 nM threshold at 30 days were 9.4, 9.6, and 9.9 nM. Figure 1 shows full data for plasma haloperidol concentrations at 30, 60, 90, and 120 days. Although there is considerable variation across strains, haloperidol levels were almost always tightly clustered within each strain-time point with the possible exception of the heaviest strain (the mean baseline weight for NZL mice was four times the lightest strain). The medians (inter-quartile ranges) of the coefficients of variation for haloperidol concentrations across strains were 0.19 (0.15–0.25) at 30 days and 0.19 (0.13–0.25) at 60 days. These data are consistent with the pilot data in Table S2 and indicate that the delivery method almost always achieved our goal of exposure to sustained human-like haloperidol steady-state concentrations.

Bottom Line: As expected, haloperidol caused marked changes in VCMs, activity in the open field and extrapyramidal symptoms (EPS).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599-7264, USA. crowley@unc.edu

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.

Show MeSH
Related in: MedlinePlus