Variation in cocaine responses across genetically diverse mouse strains

RATIONALE: Repeated exposure to psychostimulants can be followed by negative affective mood states when the drug is no longer present. These states can function as powerful negative reinforcers, intensifying drug cravings and increasing the likelihood of continued use. Although negative affective states are highly prevalent among cocaine users, and their severity is closely linked to relapse, the specific genetic factors driving these symptoms remain relatively unknown. Due to their high degree of genetic and neuroanatomical similarity to humans, and the availability of extensive reference genetic, genomic and neurobiological resources, mice provide an appropriate model for investigating the genetic basis of the behavioral traits associated with negative affective states following psychostimulant exposure. OBJECTIVE: We investigated anhedonia- and dysphoria-like behaviors following saline or cocaine exposure across the eight inbred Collaborative Cross (CC)/Diversity Outbred (DO) founder strains to evaluate their feasibility for future genetic mapping studies of cocaine response. METHODS: Mice were administered cocaine (10 mg/kg) or saline via intraperitoneal (i.p.) injections across 19 days, followed by behavioral assays to assess anhedonia- and dysphoria-like behaviors. RESULTS: We observed significant strain- and sex-dependent variation across all behavioral measures, indicating robust genetic influences on baseline affective traits, and strain-specific modulation by cocaine exposure. Heritability estimates ranged from ~ 0 to 0.86. CONCLUSIONS: Our findings demonstrate the utility of genetically diverse mouse populations for exploring the genetic underpinnings of traits relevant to negative reinforcement in cocaine use disorder (CUD) and highlight their value in modeling individual variation in negative affective states in response to cocaine.