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 model 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 selfadministered escalating doses of oxycodone under postprandial (prefed) or non-postprandial (no prefeeding) conditions. Both sexes demonstrated robust cue-induced reinstatement. In separate mice we found that oral oxycodone cues were sufficient to reinstate extinguished oral oxycodone-seeking behavior in the absence of postprandial or prior water self-administration training. During self-administration, we 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 steroid 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 1) oral drug cues are sufficient to cause reinstatement that is independent of prandial conditions and water-seeking behavior, 2) earned oral oxycodone is larger in female mice compared with male mice potentially through differences in psychomotor stimulation and drug metabolism, and 3) gonadectomy produces divergent effects on oral oxycodone self-administration between sexes.

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

“…Female rodents more rapidly acquired morphine and heroin self-administration (22,71,72), self-administered more intravenous heroin (22) and fentanyl vapor (23) in long-access selfadministration sessions, consumed more oral oxycodone during self-administration (73, 74), and had higher motivation for fentanyl (75) than males. However, females showed no difference from males in stress-induced (73) or cue-induced reinstatement for oral oxycodone (74). Opioid-dependent female mice also exhibited similar somatic signs of naloxone-precipitated heroin withdrawal to dependent male mice (22).…”

Studying Sex Differences in Rodent Models of Addictive Behavior

“…Females also drink more EtOH than males in limited‐access paradigms (Grahame, Li, & Lumeng, 1999; Melón, Wray, Moore, & Boehm, 2013; Metten, Brown, & Crabbe, 2011; Rhodes et al., 2005; Sneddon et al., 2019). Finally, some recent studies using home‐cage access paradigms to study oral opioid use have observed greater consumption in females versus males (Phillips et al., 2019; Zanni et al., 2019; but see Forgie, Beyerstein, & Alexander, 1988; Monroe & Radke, 2020).…”

A buprenorphine-validated rat model of opioid use disorder optimized to study sex differences in vulnerability to relapse

“…In general, these findings indicate that females have an enhanced sensitivity to the reinforcing effects of opioids in that they acquire heroin self-administration faster and are more motivated to obtain infusions of fentanyl, heroin, remifentanil, and morphine as compared to males (Ambrosio et al 1999 ; Carroll et al 2002 ; Cicero et al 2003 ; González et al 2003 ; Klein et al 1997 ; Lacy et al 2016 ; Lynch and Carroll 1999 ; Thorpe et al 2020 ; Townsend et al 2019 ; Vela et al 1998 ; but see Stewart et al 1996 ). Some studies have also observed higher opioid intake in females than males under short access conditions (Biscaia et al 2008 ; Carroll et al 2001 , 2002 ; Cicero et al 2003 ; Fulenwider et al 2019 ; Phillips et al 2019 ) although other studies have reported similar intake between the sexes (Gipson et al 2020 ; Mavrikaki et al 2017 ; Smethells et al 2020 ; Vazquez et al 2020 ; Zhang et al 2018 ). These preclinical results are also consistent with findings in humans showing that women with an OUD report greater positive subjective effects following opioid use than men (i.e., liking, feeling high, street value); notably, these enhanced positive reports occurred even in the face of enhanced negative subjective/physical effects (enhanced nausea and vomiting; Lofwall et al 2012 ; also see Zacny 2002 ).…”