Variation in cocaine responses across genetically diverse mouse strains

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Psychostimulant exposure can lead to negative affective states, intensifying drug cravings and relapse risk.
• These negative states are common in cocaine users and linked to relapse, but underlying genetic factors are poorly understood.
• Genetically diverse mice offer a valuable model for studying the genetic basis of these behaviors due to similarities with humans.

Purpose of the Study:

• Investigate anhedonia- and dysphoria-like behaviors in response to cocaine across eight inbred mouse strains.
• Assess the feasibility of these mouse models for future genetic mapping studies of cocaine response.
• Evaluate strain- and sex-dependent variations in behavioral responses to cocaine.

Main Methods:

• Mice from eight Collaborative Cross (CC)/Diversity Outbred (DO) founder strains were administered cocaine (10 mg/kg) or saline via intraperitoneal injection over 19 days.
• Behavioral assays were conducted post-treatment to measure anhedonia- and dysphoria-like behaviors.
• Heritability estimates were calculated to quantify genetic influence on observed traits.

Main Results:

• Significant strain- and sex-dependent variations were observed in all behavioral measures.
• These findings indicate strong genetic influences on baseline affective traits.
• Cocaine exposure modulated these traits in a strain-specific manner, with heritability estimates ranging from 0 to 0.86.

Conclusions:

• Genetically diverse mouse populations are useful for investigating the genetic basis of negative reinforcement in cocaine use disorder (CUD).
• These models effectively capture individual variations in negative affective states following cocaine exposure.
• The study highlights the importance of genetic factors in shaping responses to cocaine withdrawal.