Sex- and Dose-Dependent Differences in the Development of an Addiction-Like Phenotype Following Extended-Access Fentanyl Self-Administration

Abstract

Opioid use disorder (OUD) is a major epidemic in the United States, and fentanyl is a major culprit. The National Institute on Drug Abuse has highlighted an urgent need for research on the risks and outcomes of OUD with fentanyl; a better understanding of sex/gender differences is also critically needed given that the opioid epidemic has been particularly impactful on women. In response to this need, we developed a rat model of OUD with fentanyl and showed that sex impacts relapse vulnerability following extended-access self-administration under a low fentanyl dose. Here, our goal was to determine sex differences across a broad dose range, including high doses expected to maximize the expression of addiction-like features (e.g., vulnerability to relapse and physical dependence). Male and female rats were assigned to self-administer one of four fentanyl doses (0.25, 0.75, 1.5, and 3.0 µg/kg/infusion), and once they acquired, they were given extended (24-h/day), intermittent access (2, 5 min trials/h, fixed-ratio 1) to fentanyl for 10 days. Physical dependence (spontaneous weight loss) was assessed during early withdrawal, and relapse vulnerability was assessed on withdrawal day 15 using an extinction/cue-induced reinstatement procedure. Despite markedly higher intake in the high- versus low-dose groups, each group responded similarly during relapse testing (extinction and cue-induced reinstatement). However, number of infusions, or frequency of use, during extended access was predictive of later vulnerability to relapse, whereas total intake impacted physical dependence given that weight loss only occurred following the discontinuation of fentanyl self-administration at the three highest doses. Females self-administered more fentanyl each day and within each binge (active trial), and had longer lasting weight loss during withdrawal than males. Relapse vulnerability was also higher in females than males and highest in females tested during estrus. These findings indicate that sex is an important risk factor for patterns and levels of fentanyl intake, relapse, and physical dependence, and while fentanyl intake predicts physical dependence, frequency of use predicts relapse.

Attention bias and alcohol craving: Differential effects via biological sex and mood

“…Perhaps at low positive mood, AB leads to higher craving for woman as the “wanting” aspect of a drug becomes more robust. This is consistent with recent research indicating that women may develop addiction‐like phenotypes more rapidly than men (Towers et al, 2022). This is an important question for future investigation.…”

Effects of neonatal fentanyl on late adolescent opioid-mediated behavior

“…Unlike the fentanyl pre-treatment, sex did alter nose-poke behavior on the oral fentanyl self-administration task because female rats consistently responded at higher rates for fentanyl. This finding is in agreement with other preclinical studies showing that female rats had a greater intake of intravenous fentanyl ( Malone et al, 2021 ; Towers et al, 2022 ), heroin ( George et al, 2021 ), and oral oxycodone ( Fulenwider et al, 2020 ). Clinically, the role of sex in fentanyl and other opioid use is more complicated.…”

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

“…In clinical settings, women reportedly experience greater spontaneous ( Back et al, 2011 ) and cue-induced ( Yu et al, 2007 ; Moran et al, 2018 ) opioid craving and report more severe complications with drug use ( Hernandez-Avila et al, 2004 ; Huhn et al, 2019 ). Likewise, female rats exhibit higher extinction responding and enhanced conditioned reinstatement of heroin ( Vazquez et al, 2020 ) and fentanyl ( Towers et al, 2022 ). Furthermore, the current results show that the ability for the oxycodone-paired S D to reinstate oxycodone-seeking behavior was significantly stronger in females under vehicle conditions (50.67 ± 8.19 responses vs. 20.75 ± 3.40 responses in males).…”

“…Statistical analyses on the development and expression of oxycodone dependence were conducted separately in males and females. However, unpaired t -test were used to confirm consistency with the literature that 1) females consume more oxycodone than males and 2) females reinstate to a higher level than males ( Fulenwider et al, 2020 ; Kimbrough et al, 2020 ; Vazquez et al, 2020 ; Zanni et al, 2020 ; Towers et al, 2022 ). The acquisition of oxycodone and SCM self-administration was analyzed using two-way repeated-measures analysis of variance (RMANOVA), with session and lever (active vs. inactive) as factors.…”