Increased heroin intake and relapse vulnerability in intermittent relative to continuous self‐administration: Sex differences in rats

Abstract

Background and Purpose Studies using intermittent‐access drug self‐administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent‐ and continuous‐access self‐administration on heroin intake, patterns of self‐administration and cue‐induced heroin‐seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites. Experimental Approach Rats were trained to self‐administer a palatable solution and then heroin (0.075 mg·kg−1 per inf) either continuously (6 h·day−1; 10 days) or intermittently (6 h·day−1; 5‐min access every 30‐min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin‐seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test. Key Results Intermittent access exacerbated heroin self‐administration and was characterized by a burst‐like intake, yielding higher brain peaks of heroin and 6‐monoacetylmorphine concentrations. Moreover, intermittent access increased cue‐induced heroin‐seeking during early, but not late abstinence. Heroin‐seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle. Conclusions and Implications Intermittent heroin access in rats resembles critical features of heroin use disorder: a self‐administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder. LINKED ARTICLES This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc

Intermittent access to oxycodone decreases dopamine uptake in the nucleus accumbens core during abstinence

“…There is extensive evidence that the schedule of access engenders distinct behavioral phenotypes for cocaine self‐administration, and despite being understudied, there is evidence that this may be true for opioids as well. Indeed, a recent study found that IntA to heroin resulted in maintained seeking from abstinence day 1 to abstinence day 21 with no incubation 56 . Thus, in the current studies, rats may be expressing exaggerated seeking early in abstinence, which remains elevated later in abstinence, resulting in the absence of incubation.…”

“…Indeed, a recent study found that IntA to heroin resulted in maintained seeking from abstinence day 1 to abstinence day 21 with no incubation. 56 Thus, in the current studies, rats may be expressing exaggerated seeking early in abstinence, which remains elevated later in abstinence, resulting in the absence of incubation. Interestingly, our observation of robust oxycodone seeking both early and later in abstinence is consistent with what has been reported for human opioid craving, which is characterized by persistent opioid craving throughout abstinence and hence a lack of incubation of craving.…”

Pair housing does not alter incubation of craving, extinction, and reinstatement after heroin self-administration in female and male rats

“…However, not all studies report such differences (Lynch and Carroll, 1999; D’Ottavio et al, 2022). D’Ottavio et al (2022) found that females had increased incubation of heroin craving compared to males, but only after intermittent access, and not continuous access, heroin self-administration. Nonetheless, a recent comprehensive review surveying the field found that studies examining measures of opioid craving in rodents largely did not reveal sex differences (Nicolas et al, 2022).…”

“…For example, George et al (2021) found that female rats displayed increased responding and intake across heroin doses following 6-h heroin self-administration. However, not all studies report such differences (Lynch and Carroll, 1999;D'Ottavio et al, 2022). D'Ottavio et al (2022 found that females had increased incubation of heroin craving compared to males, but only after intermittent access, and not continuous access, heroin self-administration.…”

Time-dependent enhancement in ventral tegmental area dopamine neuron activity drives pain-facilitated fentanyl intake in males

“…This is critical from a translational perspective given that other studies examining sex differences in opioid self-administration show inconsistent results. In this regard, most studies report higher rates of opioid self-administration in females compared to males [88][89][90][91][92][93][94][95][96][97][98][99][100] while others fail to capture any sex differences [99][100][101][102] . Notably, one study found that males self-administer more oxycodone when demand is low (FR1) and this modest effect was on the number of infusions obtain rather than lever responses, suggesting that males were only slightly more efficient during the 6-s timeout periods 103 .…”