Limits...
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.

Show MeSH

Related in: MedlinePlus

Summary of dependent variables (activity, EPS, and VCMs) over all strainsEach plot shows data for one dependent variable for five time points (baseline and 30, 60, 90, and 120 days). Shown are means and SEM error bars for over all strains (square root transformation).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3117923&req=5

Figure 2: Summary of dependent variables (activity, EPS, and VCMs) over all strainsEach plot shows data for one dependent variable for five time points (baseline and 30, 60, 90, and 120 days). Shown are means and SEM error bars for over all strains (square root transformation).

Mentions: The central aim of this study was to investigate the relationship between genetic background and susceptibility to haloperidol-induced VCMs and other EPS phenotypes across 27 inbred mouse strains. Figure 2 summarizes nine dependent variables over all strains at baseline and after 30, 60, 90, and 120 days of exposure to haloperidol. Five points are noteworthy. First, the wide error bars in Figure 2 (even on a square root scale) suggest that, on average, there is considerable variation in all phenotypes across strains. Individual strain and time-point data for these nine variables indicate that between strain variation was considerably greater than within strain variation at most time points (Figure S4). Second, exposure to haloperidol had profound average effects. For example, comparing baseline with day 30, there was a 7-fold decrease in vertical activity, 263-fold increase in EPS, and 8-fold increase in overt chewing movements. Third, the baseline activity measures showed considerable variability across strains (consistent with attempts to map genetic loci for open-field activity) 24, 25. The average effect of haloperidol was maximal at day 30 or 60. Average values moved toward baseline on days 90 and 120 but did not return to baseline suggesting that the behavioral effects of haloperidol persist even when plasma concentrations are low (Table 2). Fourth, there was little average variability in EPS at baseline and the strong effects of haloperidol exposure were still present at day 120. Fifth, perhaps unlike the activity and EPS measures, the average effect of haloperidol on the four VCM measures were notably persistent through day 120 without a trend toward baseline values.


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)

Summary of dependent variables (activity, EPS, and VCMs) over all strainsEach plot shows data for one dependent variable for five time points (baseline and 30, 60, 90, and 120 days). Shown are means and SEM error bars for over all strains (square root transformation).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Summary of dependent variables (activity, EPS, and VCMs) over all strainsEach plot shows data for one dependent variable for five time points (baseline and 30, 60, 90, and 120 days). Shown are means and SEM error bars for over all strains (square root transformation).
Mentions: The central aim of this study was to investigate the relationship between genetic background and susceptibility to haloperidol-induced VCMs and other EPS phenotypes across 27 inbred mouse strains. Figure 2 summarizes nine dependent variables over all strains at baseline and after 30, 60, 90, and 120 days of exposure to haloperidol. Five points are noteworthy. First, the wide error bars in Figure 2 (even on a square root scale) suggest that, on average, there is considerable variation in all phenotypes across strains. Individual strain and time-point data for these nine variables indicate that between strain variation was considerably greater than within strain variation at most time points (Figure S4). Second, exposure to haloperidol had profound average effects. For example, comparing baseline with day 30, there was a 7-fold decrease in vertical activity, 263-fold increase in EPS, and 8-fold increase in overt chewing movements. Third, the baseline activity measures showed considerable variability across strains (consistent with attempts to map genetic loci for open-field activity) 24, 25. The average effect of haloperidol was maximal at day 30 or 60. Average values moved toward baseline on days 90 and 120 but did not return to baseline suggesting that the behavioral effects of haloperidol persist even when plasma concentrations are low (Table 2). Fourth, there was little average variability in EPS at baseline and the strong effects of haloperidol exposure were still present at day 120. Fifth, perhaps unlike the activity and EPS measures, the average effect of haloperidol on the four VCM measures were notably persistent through day 120 without a trend toward baseline values.

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