Female rats consume and prefer oxycodone more than males in a chronic two-bottle oral voluntary choice paradigm

Abstract

The increased abuse of opioids -such as oxycodone -poses major challenges for health and socioeconomic systems. Human prescription opioid abuse is marked by continuous, voluntary, oral intake, and sex differences. Therefore the field would benefit from a preclinical in-depth characterization of sex differences in a chronic oral voluntary, free choice, and continuous access paradigm. Here we show in an oral oxycodone continuous access two-bottle choice paradigm sex-dependent voluntary drug intake, dependence, and motivation to take the drug . Adult female and male Long-Evans rats were given unlimited, continuous home cage access to two bottles containing water (Control) or one bottle of water and one bottle of oxycodone dissolved in water (Experimental).Most experimental rats voluntarily drank oxycodone (~10 mg/kg/day) and escalated their intake over 22 weeks. Females self-administered twice as much oxycodone as males, leading to greater blood levels of oxycodone, and engaged in more gnawing behavior. Precipitated withdrawal revealed high levels of dependence in both sexes. Reflecting motivation to drink oxycodone, ascending concentration of citric acid suppressed the intake of oxycodone (Experimental) and the intake of water (Control); however Experimental rats returned to pre-citric acid preference levels whereas Controls rats did not. Thus, female rats consumed and preferred oxycodone more than males in this chronic two-bottle oral choice paradigm. Both sexes displayed many features of human oxycodone abuse, and behavioral pre-screening predicted parameters of intake and withdrawal. This model provides an additional paradigm for understanding mechanisms that mediate long-term voluntary drug use and for exploring potential treatment options.

Studying Sex Differences in Rodent Models of Addictive Behavior

“…In general, contemporary research indicates that female rats and mice are more susceptible to drug self-administration than males. This pattern of female vulnerability is observed in home-cage drinking (Rhodes et al, 2005;Sneddon, White, & Radke, 2019;Zanni et al, 2019) during the acquisition, maintenance/escalation, and reinstatement phases of operant self-administration (Anker & Carroll, 2011;Lynch et al, 2002), as well as in models of aversion resistance (Monroe & Radke, 2020;Radke, Held, Sneddon, Riddle, & Quinn, 2020;Sneddon et al, 2020;Radke, Sneddon, Frasier, & Hopf, 2021).…”

“…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).…”