Genetic risk for schizophrenia modulates WIN 55,212-2 reward: Evidence from a heterozygous transmembrane domain neuregulin 1 mutant mouse model

BACKGROUND: Cannabis abuse rates are up to ten times higher in individuals with schizophrenia than the general population, but it is unclear what is driving this high level of comorbidity. Genetic predisposition for schizophrenia may increase the risk of cannabis abuse; however, there is limited empirical support for this. METHODS: We investigated this question using a well-established genetic mouse model of schizophrenia risk, the heterozygous transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mouse, which also shows behavioural and neural susceptibility to cannabis components. WIN 55,212-2 (WIN), a cannabinoid 1 (CB1) receptor agonist, was used to model the rewarding and aversive properties of cannabis. We first validated a conditioned place preference protocol to determine rewarding and aversive doses of WIN administration in C57BL/6J mice, the background strain of our schizophrenia mouse model. We then investigated the effects of these WIN dose regimes on place preference and locomotion in male and female Nrg1 TM HET mice and their control wildtype-like littermates. RESULTS: We found that low dose WIN (0.1 mg/kg) was rewarding in wildtype-like, but not in Nrg1 TM HET mice of both sexes. Conversely, male and female mice of both genotypes found high dose WIN (3 mg/kg) aversive. While all mice showed a similar locomotor response to low dose WIN administration, male Nrg1 TM HET mice showed an earlier development of locomotor tolerance to high dose WIN, with no differences in WIN-induced locomotor sedation in female mice. CONCLUSION: Our findings suggest that genetic risk for schizophrenia can modulate the rewarding properties of the CB1 receptor agonist WIN and support the hypothesis that comorbidity between schizophrenia and cannabis use disorder may in part be driven by shared genetic risk factors.