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

Paola Giusti-Rodríguez1, James G Xenakis1, James J Crowley1

  • 1Department of Genetics, University of North Carolina, Chapel Hill, NC.

G3 (Bethesda, Md.)
|July 23, 2020
PubMed
Summary
This summary is machine-generated.

Genetic diversity in mice reveals susceptibility to antipsychotic side effects, mirroring human tardive dyskinesia. This research paves the way for developing safer schizophrenia treatments by understanding adverse drug reactions.

Keywords:
MPPMultiparent Advanced Generation Inter-Cross (MAGIC)multiparental populations

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Genetics

Background:

  • Schizophrenia affects 1% of the population, treated with antipsychotics.
  • Antipsychotics have side effects; chronic haloperidol causes tardive dyskinesia (TD) in 30% of patients.
  • Mice models exhibit TD-like symptoms, including vacuous chewing movements (VCMs).

Purpose of the Study:

  • To investigate the genetic underpinnings of antipsychotic-induced adverse drug reactions (ADRs).
  • To utilize genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice for this study.

Main Methods:

  • Administered haloperidol or placebo to 840 RIX mice from 73 lines.
  • Conducted a battery of behavioral tests to monitor ADR development.
  • Employed linear mixed models to analyze strain and treatment effects.

Main Results:

  • Significant strain effects (P < 0.001) were observed across most behavioral measurements.
  • Strong strain-by-treatment interactions influenced phenotypes like distance traveled, vertical activity, and extrapyramidal symptoms (EPS).
  • RIX mice showed VCMs at a rate (~30%) similar to human TD incidence.

Conclusions:

  • Genetic factors significantly influence susceptibility to antipsychotic-induced ADRs in mice.
  • Mouse models can elucidate the genetic basis of ADRs, aiding in developing safer schizophrenia therapies.
  • Understanding genetic predispositions can lead to personalized and safer antipsychotic treatments.