Ranking the contribution of behavioral measures comprising oxycodone self-administration to reinstatement of drug-seeking in male and female rats

Abstract

IntroductionRates of relapse to drug use during abstinence are among the highest for opioid use disorder (OUD). In preclinical studies, reinstatement to drug-seeking has been extensively studied as a model of relapse–but the work has been primarily in males. We asked whether biological sex contributes to behaviors comprising self-administration of the prescription opioid oxycodone in rats, and we calculated the relative contribution of these behavioral measures to reinstatement in male and female rats.Materials and methodsRats were trained to self-administer oxycodone (8 days, training phase), after which we examined oxycodone self-administration behaviors for an additional 14 days under three conditions in male and female rats: short access (ShA, 1 h/d), long access (LgA, 6 h/d), and saline self-administration. All rats were then tested for cue-induced reinstatement of drug-seeking after a 14-d forced abstinence period. We quantified the # of infusions, front-loading of drug intake, non-reinforced lever pressing, inter-infusion intervals, escalation of intake, and reinstatement responding on the active lever.ResultsBoth male and female rats in LgA and ShA conditions escalated oxycodone intake to a similar extent. However, males had higher levels of non-reinforced responding than females under LgA conditions, and females had greater levels of reinstatement responding than males. We then correlated each addiction-related measure listed above with reinstatement responding in males and females and ranked their respective relative contributions. Although the majority of behavioral measures associated with oxycodone self-administration did not show sex differences on their own, when analyzed together using partial least squares regression, their relative contributions to reinstatement were sex-dependent. Front-loading behavior was calculated to have the highest relative contribution to reinstatement in both sexes, with long and short inter-infusion intervals having the second greatest contribution in females and males, respectively.DiscussionOur results demonstrate sex differences in some oxycodone self-administration measures. More importantly, we demonstrate that a sex- dependent constellation of self-administration behaviors can predict the magnitude of reinstatement, which holds great promise for relapse prevention in people.

Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking

“…We observed no sex differences in oxycodone intravenous self-administration, consistent with reports in Sprague Dawley and other rat strains 47 , 63 , with the exception of female Wistars which self-administer a greater number of infusions than males 48 . Despite no differences in oxycodone intake, increased cued seeking after two 63 , but not four weeks of home cage abstinence 47 has been reported in Sprague Dawley females relative to males. Here, sex-differences in cued oxycodone seeking were only observed in the alcohol condition.…”

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

“…In the present study, the "loading" phase observed within the first 30 minutes may indicate an increased drug intake due to the emergence of negative emotional-like states associated with withdrawal. This behavior aligns with the theory that negative reinforcement mechanisms drive excessive drug intake to alleviate discomfort from withdrawal (3,44,45) and is consistent with previous findings in a rat model of oxycodone selfadministration that observed front-loading behavior (46).…”

Δ9-tetrahydrocannabinol (THC) Increases the Rewarding Value of Oxycodone During Self-Administration in Rats

“…There was no significant difference between the Cohort 2 and 3 male and female rats in oxycodone IVSA acquisition (Supplementary Figure S2), and the slightly poorer discrimination of the males was due to them making more active lever presses during time-out intervals, similar to a prior report (Guha et al, 2022). Increased oxycodone self-administration by female rats has been observed in 8-12 h session IVSA in some prior studies (Kimbrough et al, 2020;Nguyen et al, 2020a), but not in others (Illenberger et al, 2023a).…”

“…While the short access condition has significant strengths as a model of acute drug reward, it may not best address the ongoing cycle of intoxication / withdrawal that leads to an addictive use disorder (Koob, 2022; Koob and Le Moal, 2001). Extended access to intravenous self-administration of opioids leads to escalating intake and numerous alterations of brain and behavior that are consistent with an opioid use disorder (Ahmed et al, 2000; Blackwood et al, 2019b; Fu et al, 2022; Guha et al, 2022; Kenny et al, 2006; Kimbrough et al, 2020; Matzeu and Martin-Fardon, 2020; Salisbury et al, 2020).…”