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Quantitative trait loci affecting methamphetamine responses in BXD recombinant inbred mouse strains
J E Grisel1, J K Belknap, L A O'Toole
1Research Service, Veterans Affairs Medical Center, Portland, OR 97201, USA.
Summary
Genetic factors significantly influence responses to methamphetamine (METH). Quantitative trait locus (QTL) mapping identified genetic markers associated with METH sensitivity and behaviors, revealing potential shared neural pathways for psychostimulant responses.
Area of Science:
- Neurogenetics
- Behavioral Pharmacology
- Genomics
Background:
- Individual responses to abused drugs, including methamphetamine (METH), are influenced by complex genetic and environmental interactions.
- Classical genetic analyses struggle to elucidate the genetic underpinnings of drug abuse-related phenotypes.
- Quantitative trait locus (QTL) mapping offers a powerful approach to identify genetic contributions to complex traits by linking genetic markers to phenotypic variations.
Purpose of the Study:
- To investigate the genetic basis of behavioral and physiological responses to methamphetamine (METH) in a mouse model.
- To identify specific quantitative trait loci (QTLs) associated with varying sensitivity to METH across different behavioral measures.
- To explore potential overlaps in genetic influences on responses to METH and other psychostimulants.
Main Methods:
- Utilized C57BL/6J, DBA/2J, and 25 BXD recombinant inbred (RI) mouse strains to assess behavioral and physiological responses to multiple METH doses.
- Measured stereotyped chewing, horizontal home cage activity, body temperature changes, and stereotyped climbing behavior following METH administration.
- Employed QTL mapping to associate allelic variation at microsatellite genetic markers with METH sensitivity phenotypes (p < 0.01).
Main Results:
- Provisionally identified QTLs for various METH-induced phenotypes, with some QTLs specific to certain behaviors and others influencing multiple responses.
- Detected significant associations between METH sensitivity and allelic status at multiple genetic markers.
- Candidate gene analyses suggested involvement of neurotransmitter systems, including acetylcholine and glutamate.
Conclusions:
- Genetic factors play a significant role in modulating individual differences in responses to methamphetamine.
- QTL mapping successfully identified genetic loci influencing diverse METH-related behaviors and physiological changes.
- Overlapping QTLs across different psychostimulant responses suggest shared genetic architectures and neural substrates for some drug effects.