Intermittent access heroin self-administration increases drug intake in both sexes and relapse vulnerability in female rats

Drug seeking progressively increases during abstinence (incubation of drug craving). Most studies of this phenomenon used continuous access drug self-administration procedures. Recently, studies using intermittent access drug self-administration procedures showed increased motivation to self-administer and seek drugs. We compared the effects of intermittent and continuous access heroin self-administration on heroin intake, patterns of heroin self-administration, modeled brain levels of heroin and its active metabolites, and incubation of craving after forced or voluntary abstinence. We trained male and female rats to self-administer a palatable solution and then heroin (0.075 mg/kg/inf) either continuously (6-h/d; 10 d) or intermittently (6-h/d; 5-min access/30-min; 10 d). Next, we assessed heroin seeking after 1 or 21 abstinence days. Between tests, the rats underwent either home cage forced abstinence or food choice-induced voluntary abstinence. We modeled brain levels of heroin and its metabolites during drug self-administration and measured the female estrous cycle after the relapse tests. Intermittent heroin access increased drug intake, induced higher spikes of heroin and 6-monoacetylmorphine brain levels and increased heroin seeking during early, but not late abstinence. In both sexes, continuous access to heroin determine incubation of craving after forced, but not voluntary abstinence. Heroin seeking was higher in females after intermittent but not continuous drug self-administration. This effect was independent of the estrous cycle phase. Intermittent heroin access in rats mimic critical features of heroin addiction: binge-like intake and high relapse vulnerability during early abstinence. Intermittent binge-like heroin intake may make females more susceptible to relapse than males.