Impact of sex on heroin intravenous self-administration by heterogeneous stock rats

Background Intravenous self-administration (IVSA) of opioids by rats has been shown frequently to exhibit no sex differences, in many cases a higher intake of females, and only rarely higher rates in males. A diversity of methodological parameters (opioid identity, training doses, rat strain, session duration) makes it difficult to identify consistent contributions to these outcomes. Objective To determine if Heterogeneous Stock (HS) rats derived from 8 founder strains differ by sex in the IVSA of opioids. Methods Male and female Heterogeneous Stock ( N = 7–8 per sex) rats were permitted to self-administer heroin (20 µg/kg/infusion) in 2 h sessions under a Fixed Ratio 1 schedule of reinforcement. After acquisition, animals completed sessions in which different infusion doses of heroin (0, 15, 30, 60, 120 µg/kg/infusion), oxycodone (0, 30, 60, 150, 300 µg/kg/infusion) and fentanyl (0, 0.625, 1.25, 2.5, 5.0 µg/kg/infusion) were assessed. Next, animals were evaluated on doses of heroin (15, 30, 60, 120 µg/kg/infusion), oxycodone (30, 60, 150, 300 µg/kg/infusion) and fentanyl (0.625, 1.25, 2.5, 5.0 µg/kg/infusion) under a Progressive Ratio schedule. Anti-nociceptive effects of heroin (0.56–2.4 mg/kg, s.c.) were examined with a warm water tail-withdrawal assay. Results Female HS rats consistently self-administered more infusions of opioids, including heroin during acquisition, all three opioids during FR-1 dose substitution and of oxycodone and fentanyl in the PR procedure. Male rats were moderately more sensitive to the anti-nociceptive effects of heroin. Conclusions Female rats drawn at random from a genetically diverse population self-administer opioids at higher rates than their male counterparts.