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, theneuregulin 1transmembrane domain heterozygous (Nrg1 TMHET) mouse.MethodsWe examined drug-induced locomotor sensitization and conditioned place preference for several cocaine doses (5, 10, 20, 30 mg/kg) in male adultNrg1 TMHET 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 betweenNrg1 TMHET mice and WT littermates at all doses tested. Locomotor sensitization to cocaine was not affected byNrg1genotype at any dose. Although self-administration and motivation for cocaine was unaffected, extinction of cocaine self-administration was impaired inNrg1 TMHET compared to WT controls, and cue-induced reinstatement was greater inNrg1mutants 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 inNrg1 TMHET mice compared to WTs.DiscussionThese results suggest impaired response inhibition for cocaine inNrg1 TMHET mice and suggestsNrg1mutation may contribute to behaviours which can limit control over cocaine use.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00213-023-06386-8.