Impaired extinction of operant cocaine in a genetic mouse model of schizophrenia risk

BackgroundIndividuals with schizophrenia have high rates of comorbid substance use problems. One potential explanation for this comorbidity is similar neuropathophysiology in substance use and schizophrenia, which may arise from shared genetic risk factors between the two disorders. Here we investigated if genetic risk for schizophrenia could affect drug reward and reinforcement for cocaine in an established mouse model of genetic risk for schizophrenia, the neuregulin 1 transmembrane domain heterozygous (Nrg1 TM HET) mouse.MethodsWe examined drug-induced locomotor sensitization and conditioned place preference for several cocaine doses (5, 10, 20, 30 mg/kg) in male adult Nrg1 TM HET and wild-type-like (WT) littermates. We also investigated intravenous self-administration of and motivation for cocaine (doses 0.1, 0.5, 1 mg/kg/infusion), as well as extinction and cue-induced reinstatement of cocaine. In a follow-up experiment, we examined self-administration, extinction and cue-induced reinstatement of a natural reward, oral sucrose.ResultsCocaine preference was similar between Nrg1 TM HET mice and WT littermates at all doses tested. Locomotor sensitization to cocaine was not affected by Nrg1 genotype at any dose. Although self-administration and motivation for cocaine was unaffected, extinction of cocaine self-administration was impaired in Nrg1 TM HET compared to WT controls, and cue-induced reinstatement was greater in Nrg1 mutants in the middle of the reinstatement session. Sucrose self-administration and extinction thereof was not affected by genotype, but inactive lever responding was elevated during cue-induced reinstatement for operant sucrose in Nrg1 TM HET mice compared to WTs.DiscussionThese results suggest impaired response inhibition for cocaine in Nrg1 TM HET mice and suggests Nrg1 mutation may contribute to behaviours which can limit control over cocaine use.

Automated summary

The study investigates if genetic risk for schizophrenia affects drug reward and reinforcement for cocaine. The results suggest that Nrg1 mutation impairs response inhibition for cocaine and limits control over its use.