Opioid Withdrawal Produces Sex-Specific Effects on Fentanyl-Versus-Food Choice and Mesolimbic Transcription

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

“…These findings are consistent with our previous study with fentanyl self-administration under these extended-access conditions ( Bakhti-Suroosh et al, 2021 ) and previous work with heroin showing robust sex differences in intake during extended-access self-administration under lower dose conditions (30 and 60 μg/kg/infusion; Towers et al, 2019 ), but not higher dose conditions (250 μg/kg/infusion; Zhang et al, 2015 ). These findings also provide insight as to why a few studies using higher doses of opioids have reported no sex differences in levels of opioid intake under extended-access conditions with heroin (100 μg/kg/infusion; Venniro et al, 2017 ; Venniro et al, 2019 ) and fentanyl (3.2 μg/kg/infusion, Townsend et al, 2021 ; 2.5 μg/kg/infusion, Hammerslag et al, 2021 , Reiner et al, 2020 ). One exception was for binge intake, where females had higher intake than males regardless of dose.…”

“…This conclusion is supported by findings in humans showing that a substantial subgroup of people with OUD have relatively low levels of physical dependence ( Kanof et al, 1991 ). Interestingly, a recent preclinical study ( Townsend et al, 2021 ) also showed that despite similarities between men and women for both escalation of fentanyl intake and physical dependence, only the men developed an enhanced preference for fentanyl over a nondrug alternative reinforcer (Ensure). This is important because this shift is believed to represent another key feature of OUD in humans, an enhanced preference for a drug to the exclusion of other reinforcing stimuli and activities and further supports the notion that features of the addiction-like phenotype develop independently of one another.…”

“…One exception was for binge intake, where females had higher intake than males regardless of dose. This is interesting because it suggests that even under high-dose conditions where intake is similar between males and females ( Venniro et al, 2017 ; Venniro et al, 2019 ; Reiner et al, 2020 ; Hammerslag et al, 2021 ; Townsend et al, 2021 ), there is likely a sex difference in the pattern of self-administration. Indeed, numerous studies have shown that there are sex differences in patterns of extended-access drug self-administration under both high and low dose conditions (e.g., Lynch and Taylor, 2004 ; Towers et al, 2019 ) with female rodents self-administering more heroin during the first hour of a long, continuous access session (fixed-ratio 1, 6-h session; Towers et al, 2019 ), having a longer initial period of “binge” cocaine before taking a break and showing a more diurnal dysregulation pattern of cocaine use during 24-h/day sessions (Lynch and Taylor, 2004), and having greater binge-like alcohol drinking using a two-bottle, limited-access “drinking-in-the-dark” procedure ( Sneddon et al, 2019 ) compared with males.…”

“…Females also showed an enhanced sensitivity to the anorectic effect of the low dose of fentanyl during extended-access self-administration. Most preclinical self-administration studies use 6- or 12-h extended-access sessions, which result in daily cycles of intake and withdrawal that are long enough to induce weight changes due to physical dependence ( Townsend et al, 2021 ). This is the first study, to our knowledge, that has monitored changes in body weight in males and females over a period of 24-h/day opioid access followed by prolonged withdrawal.…”

“…Thus, in the current study, we examined fentanyl self-administration across a broad range of fentanyl doses (0.25, 0.75, 1.5, and 3.0 µg/kg/infusion) and hypothesized that relapse vulnerability would be highest following high-dose fentanyl self-administration. We also expanded our model to include an additional key feature of OUD in humans, physical dependence ( American Psychiatric Association, 2013 ), as assessed by spontaneous weight loss during early withdrawal, a highly predictive single factor of withdrawal ( Cicero and Meyer, 1973 ; Gellert and Holtzman, 1978 ; Nickel and Aledter, 1987 ; Maldonado et al, 1992 ; Houshyar et al, 2004 ; Navarro-Zaragoza et al, 2010 ; Pintér-Kübler et al, 2013 ; Bobzean et al, 2019 ; Seaman and Collins, 2021 ; Townsend et al, 2021 ). Physical dependence is a defining feature of OUD in humans ( American Psychiatric Association, 2013 ), and women experience a more severe withdrawal syndrome than men ( Huhn and Dunn 2020 ).…”