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Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)

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...

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Autores principales: Giusti-Rodríguez, Paola, Xenakis, James G., Crowley, James J., Nonneman, Randal J., DeCristo, Daniela M., Ryan, Allison, Quackenbush, Corey R., Miller, Darla R., Shaw, Ginger D., Zhabotynsky, Vasyl, Sullivan, Patrick F., Manuel de Villena, Fernando Pardo, Zou, Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Genetics Society of America 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466989/
https://www.ncbi.nlm.nih.gov/pubmed/32694196
http://dx.doi.org/10.1534/g3.120.400975
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author Giusti-Rodríguez, Paola
Xenakis, James G.
Crowley, James J.
Nonneman, Randal J.
DeCristo, Daniela M.
Ryan, Allison
Quackenbush, Corey R.
Miller, Darla R.
Shaw, Ginger D.
Zhabotynsky, Vasyl
Sullivan, Patrick F.
Manuel de Villena, Fernando Pardo
Zou, Fei
author_facet Giusti-Rodríguez, Paola
Xenakis, James G.
Crowley, James J.
Nonneman, Randal J.
DeCristo, Daniela M.
Ryan, Allison
Quackenbush, Corey R.
Miller, Darla R.
Shaw, Ginger D.
Zhabotynsky, Vasyl
Sullivan, Patrick F.
Manuel de Villena, Fernando Pardo
Zou, Fei
author_sort Giusti-Rodríguez, Paola
collection PubMed
description 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.
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spelling pubmed-74669892020-09-14 Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX) Giusti-Rodríguez, Paola Xenakis, James G. Crowley, James J. Nonneman, Randal J. DeCristo, Daniela M. Ryan, Allison Quackenbush, Corey R. Miller, Darla R. Shaw, Ginger D. Zhabotynsky, Vasyl Sullivan, Patrick F. Manuel de Villena, Fernando Pardo Zou, Fei G3 (Bethesda) Multiparental Populations 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. Genetics Society of America 2020-07-20 /pmc/articles/PMC7466989/ /pubmed/32694196 http://dx.doi.org/10.1534/g3.120.400975 Text en Copyright © 2020 Giusti-Rodriguez et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Multiparental Populations
Giusti-Rodríguez, Paola
Xenakis, James G.
Crowley, James J.
Nonneman, Randal J.
DeCristo, Daniela M.
Ryan, Allison
Quackenbush, Corey R.
Miller, Darla R.
Shaw, Ginger D.
Zhabotynsky, Vasyl
Sullivan, Patrick F.
Manuel de Villena, Fernando Pardo
Zou, Fei
Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)
title Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)
title_full Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)
title_fullStr Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)
title_full_unstemmed Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)
title_short Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)
title_sort antipsychotic behavioral phenotypes in the mouse collaborative cross recombinant inbred inter-crosses (rix)
topic Multiparental Populations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466989/
https://www.ncbi.nlm.nih.gov/pubmed/32694196
http://dx.doi.org/10.1534/g3.120.400975
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