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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
Summary
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.
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.
