Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats exhibit a dysregulation of the opioid system in several brain areas and show innate psychiatric traits comorbid with drug abuse. Therefore, we hypothesized that, similar to alcohol, msP would display increased preference for heroin compared to non-preferring Wistar controls. Thus, we compared the heroin self-administration (HSA) dose/response (1, 7, 20, 60 µg/infusion) curves of msP and Wistar rats under fixed-ratio 1(FR1) and progressive ratio (PR) contingencies. Male msP rats, showed increased HSA at intermediate doses under both FR and PR contingencies. Females msPs only showed higher motivation for the three higher doses under PR contingency. A real time PCR analysis revealed that heroin naïve male, but not female, msP rats show increased MOP relative gene expression in the ventral tegmental area (VTA). To verify if the innate overexpression of MOP in the VTA plays a role in male msP’s increased heroin preference, we toned down VTA MOP expression in both msP and Wistar rats by local transfection of a MOP short hairpin RNA (MOPshRNA) construct. MOPshRNA msP rats showed a reduction in HSA under FR1 contingency at both heroin doses tested (7, 20 µg/infusion). A similar effect was observed in Wistars only at the lowest heroin dose. No differences were observed under PR contingency or in the SA of the natural reward saccharin. Our data demonstrated that msP rats show increased heroin consumption and motivation, and that in males the increased consumption is linked to elevated MOP gene expression in the VTA.