Oral prescription opioid‐seeking behavior in male and female mice

Abstract

A significant portion of prescription opioid users self-administer orally rather than intravenously. Animal models of opioid addiction have demonstrated that intravenous cues are sufficient to cause drug seeking. However, intravenous models may not characterize oral users, and the preference to self-administer orally appears to be partially influenced by the user's sex. Our objectives were to determine whether oral opioid-associated cues are sufficient for relapse and whether sex differences exist in relapse susceptibility. Mice orally self-administered escalating doses of oxycodone under postprandial (prefed) or non-postprandial (no prefeeding) conditions. Both sexes demonstrated cue-induced reinstatement following abstinence. In separate mice, we found that oral oxycodone cues were sufficient to reinstate extinguished oral oxycodone-seeking behavior following abstinence without prior postprandial or water self-administration training. During self-administration, we incidentally found that female mice earned significantly more mg/kg oxycodone than male mice. Follow-up studies indicated sex differences in psychomotor stimulation and plasma oxycodone/oxymorphone following oral oxycodone administration. In addition, gonadal studies were performed in which we found divergent responses where ovariectomy-enhanced and orchiectomy-suppressed oral self-administration. While the suppressive effects of orchiectomy were identified across doses and postprandial conditions, the enhancing effects of ovariectomy were selective to non-postprandial conditions. These studies establish that (a) oral drug cues are sufficient to cause reinstatement that is independent of prandial conditions and water-seeking behavior, (b) earned oral oxycodone is larger in female mice compared with male mice potentially through differences in psychomotor stimulation and drug metabolism, and (c) gonadectomy produces divergent effects on oral oxycodone self-administration between sexes.

Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice

“…In our study, female mice reliably consume more fentanyl than male mice, even when provided free choice throughout. This finding aligns well with recent work showing female mice are resistant to devaluation of oral fentanyl ( Monroe and Radke, 2021 ), self-administer more oral oxycodone ( Phillips et al, 2020 ), intravenous heroin ( Towers et al, 2019 ), and remifentanil ( Anderson et al, 2021 ). Further work is needed to establish if stress exacerbates the sex-differences in operant opioid self-administration.…”

Extended access to fentanyl vapor self-administration leads to addiction-like behaviors in mice: Blood chemokine/cytokine levels as potential biomarkers

“…Here, in male and female mice, 6 h access to vaporized fentanyl was sufficient to produce an escalation of intake over time, and these mice exhibited an increase in dependence as defined by naloxone-precipitated opioid withdrawal. We did not observe major sex differences in opioid intake or the rate of escalation ( Supplemental Tables S1 , S2 ), which contrasts with findings in mice that self-administered heroin intravenously or oxycodone orally, in which females had higher overall intake [ 15 , 44 ]. One potential explanation for this difference is drug-specific sex differences (e.g., [ 45 ]).…”

Oral oxycodone self‐administration leads to features of opioid misuse in male and female mice

“…2,[95][96][97][98][99] While pharmacokinetic influences on sex differences are beyond the scope of our study, plasma concentrations of OXY and its active metabolite oxymorphone were influenced by sex, presence of sex organs and feeding conditions and were exacerbated following repeated administrations. 2 This likely arises because OXY metabolism is mediated largely by CYP3A4 and CYP2D6, 100,101 whose activity is modulated by sex hormones and food intake. 102,103 However, sex effects on OXY pharmacokinetics were either diminished or not observed with intravenous administration, 104,105 highlighting the importance of route of administration for studying sex differences in preclinical studies.…”

“…[32][33][34][35][36] Yet, prior models of oral opioid self-administration have taken place in novel contexts (e.g., operant chamber) and under food restriction. [2][3][4] Thus, modelling continuous prescription opioid access in a familiar environment may provide a more clinically relevant comparison to prescription opioid self-administration.…”