Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)
Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)
ABSTRACT Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.
Zhabotynsky Vasyl、DeCristo Daniela M.、Giusti-Rodr¨aguez Paola、Xenakis James G.、Crowley James J.、Quackenbush Corey R.、Shaw Ginger D.、Zou Fei、Ryan Allison、Miller Darla R.、Sullivan Patrick F.、Nonneman Randal J.、de Villena Fernando Pardo-Manuel
Department of Biostatistics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North Carolina||Department of Biostatistics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North Carolina||Department of Psychiatry, University of North Carolina||Department of Medical Epidemiology and Biostatistics, Karolinska InstitutetDepartment of Genetics, University of North CarolinaDepartment of Genetics, University of North Carolina||Lineberger Comprehensive Cancer Center, University of North Carolina
神经病学、精神病学基础医学医学研究方法
Zhabotynsky Vasyl,DeCristo Daniela M.,Giusti-Rodr¨aguez Paola,Xenakis James G.,Crowley James J.,Quackenbush Corey R.,Shaw Ginger D.,Zou Fei,Ryan Allison,Miller Darla R.,Sullivan Patrick F.,Nonneman Randal J.,de Villena Fernando Pardo-Manuel.Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/761353.点此复制
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