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

Drug seeking gradually increases during abstinence (incubation of craving). Most studies of this phenomenon used continuous access self-administration procedures. Recently, studies using intermittent access self-administration procedure, showed increased motivation to take and seek drugs. We compared the effect of these two procedures on heroin intake, pattern of self-administration, modeled brain levels of heroin and its 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) either continuously (6-h/d; 10d) or intermittently (6-h/d; 5-m/30-m; 10d). Next, we tested heroin seeking after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. We modeled brain levels of heroin and its metabolites during self-administration and assessed female estrous cycle after relapse tests. Intermittent access increased heroin intake, induced higher spikes of heroin and 6-acetylmorphine brain levels and increased heroin seeking in early abstinence. In both sexes, continuous access determined incubation of craving after forced, but not voluntary abstinence. Heroin seeking was higher in females after intermittent but not continuous access, independently of the estrous cycle phase. Intermittent access mimics critical features of heroin addiction: drug bingeing and high relapse in early abstinence.