Oxycodone self-administration and withdrawal behaviors in male and female Wistar rats

Abstract

Over the last decade oxycodone has become one of the most widely abused drugs. The emergence of oxycodone dependence as a serious health crisis has prompted a major need for animal models of oxycodone dependence with face and predictive validity. Oxycodone use in humans is more prevalent in women (Administration, 2014) and leads to pronounced hyperalgesia and irritability. However, it is unclear if the current animal model of oxycodone self-administration recapitulates these characteristics. We assessed the face validity of an extended access oxycodone self-administration model in rats by examining escalation of oxycodone intake and behavioral symptoms of withdrawal including irritability like behavior and mechanical nociception in male and female rats. We found that male and female rats escalated oxycodone intake over the course of 14 self-administration sessions, however, female rats escalated took more drug than male rats once escalated. When we assessed irritability-like behavior we found no differences between baseline or withdrawal, however when tested immediately after a 12-h self-administration session rats showed a decreased number of aggressive responses and a increased number of defensive responses. When tested for mechanical threshold during withdrawal rats showed pronounced hyperalgesia that was only partially reversed by oxycodone self-administration. The results of the present study demonstrate the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and demonstrating pronounced changes to pain and affective states.

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

“…These findings are consistent with findings showing that women with an OUD are more motivated to obtain opioids (e.g., greater drug and sexual risk behaviors; Meade et al 2010 ), show a faster time-course to the development of an OUD (Hernandez-Avila et al 2004 ), and have higher levels of craving during abstinence as compared to men with an OUD (Back et al 2011a ; Kennedy et al 2013 ; Moran et al 2018 ; Yu et al 2007 ). They are also consistent with previous preclinical findings showing that females self-administer more heroin and oxycodone under extended access conditions than males (Carroll et al 2002 ; Towers et al 2019 ; Kimbrough et al 2020 ) and with previous findings with other drugs of abuse showing that females have higher levels of drug-seeking than males following extended access self-administration and abstinence (Lynch 2018 ). Our current findings showing that sex differences were apparent in some conditions, but not others, may also explain some discrepancies in the occurrence of sex differences under extended access conditions (e.g., Carroll et al 2002 ; Towers et al 2019 ; Kimbrough et al 2020 ; Reiner et al 2020 ; Fredriksson et al 2020 ; Venniro et al 2017 , 2019 ) since differences are likely to depend on both the training and extended access conditions.…”

“…They are also consistent with previous preclinical findings showing that females self-administer more heroin and oxycodone under extended access conditions than males (Carroll et al 2002 ; Towers et al 2019 ; Kimbrough et al 2020 ) and with previous findings with other drugs of abuse showing that females have higher levels of drug-seeking than males following extended access self-administration and abstinence (Lynch 2018 ). Our current findings showing that sex differences were apparent in some conditions, but not others, may also explain some discrepancies in the occurrence of sex differences under extended access conditions (e.g., Carroll et al 2002 ; Towers et al 2019 ; Kimbrough et al 2020 ; Reiner et al 2020 ; Fredriksson et al 2020 ; Venniro et al 2017 , 2019 ) since differences are likely to depend on both the training and extended access conditions. As with the current findings, these previous reports of sex differences in drug-seeking have typically revealed effects during extinction, but not following exposure to drug-associated cues (Lynch 2018 ).…”

“…Results with other drugs of abuse demonstrate that in females, these characteristics are more robustly expressed (Nicolas et al 2019 ; Reichel et al 2012 ) and develop sooner during abstinence and/or following less drug exposure as compared to males (Lynch and Taylor 2004 ; Ramôa et al 2013 , 2014 ; Perry et al 2013 ; Lynch 2018 ). Similar effects may also occur with opioids considering findings showing that female rats and mice given extended access (≥ 6 h/day) to heroin or oxycodone self-administer more drug and/or show greater escalation of intake over time than their male counterparts (Carroll et al 2002 ; Towers et al 2019 ; Kimbrough et al 2020 ). However, sex differences with opioids may be less robust than with other drugs given that several other studies have reported no differences between males and females in levels or patterns of drug intake under extended access conditions (Venniro et al 2017 , 2019 ; Reiner et al 2020 ) or for subsequent levels of drug-seeking following voluntary (Reiner et al 2020 ) or forced abstinence (Venniro et al 2019 ).…”

Opioid withdrawal produces sex-specific effects on fentanyl-vs.-food choice and mesolimbic transcription

“…The present results are consistent with previous opioid escalation studies in male rats (31). However, the present results are in contrast to reports of female rodents showing greater rates of opioid escalation than males (24, 32-34) in some studies, but not all (35-37). Reasons for inconsistent sex differences in rates of opioid self-administration are not presently clear and could reflect differences in either the self-administered opioid or other experimental conditions.…”

Paradoxical changes in brain reward status during oxycodone self-administration in a novel test of the negative reinforcement hypothesis

“…Sex differences in oral (Fulenwider et al, 2020; Zanni, DeSalle, Deutsch, Barr & Eisch, 2020) and intravenous (Kimbrough et al, 2020; Nguyen, Creehan, Kerr & Taffe, 2020) oxycodone intake have been reported in rats, although another study found no sex difference in sustained IVSA of oxycodone under varying training conditions (Mavrikaki, Pravetoni, Page, Potter & Chartoff, 2017). Interestingly, even when sex differences in IVSA under fixed-ratio conditions were reported, there were no sex differences under a progressive ratio dose substitution (Nguyen, Creehan, Kerr & Taffe, 2020) or in withdrawal-induced behaviors (Kimbrough et al, 2020), suggesting similar motivation and similar induction of negative affect across sexes. Finally, Mavrikaki and colleagues have recently shown that prior to exposure to chronic morphine injections may differentially affect acquisition of oxycodone IVSA in males compared to females (Mavrikaki, Lintz, Constantino, Page & Chartoff, 2020).…”