Effects of voluntary exercise and sex on multiply-triggered heroin reinstatement in male and female rats

Abstract

Background-The rise in heroin addiction has heightened the need for novel and effective treatments. Physical exercise has been shown as an effective treatment for stimulant abuse in clinical and pre-clinical research. However, this treatment has not yet been tested on opioid addiction. This study examined the effects of physical activity (wheel running) on heroin-seeking in rats within a reinstatement paradigm (i.e., heroin relapse model).Methods-Female and male rats were trained to self-administer intravenous heroin (0.015 mg/ kg). Once trained, rats were placed into extinction (i.e., heroin abstinence) for 21 days with continuous access to a locked or unlocked running wheel. After extinction, rats were tested for drug-(heroin, caffeine, and yohimbine) and cue-primed reinstatement of heroin-seeking.Results-Females completed more wheel revolutions than males across all study phases. Access to an unlocked running wheel reduced extinction and reinstatement of heroin-seeking, with greater reductions in females than males across several reinstatement conditions. In the locked wheel group, female rats showed greater reinstatement of heroin-seeking than males across several priming conditions.Conclusions-Wheel running reduced heroin-seeking in male and female rats, with females showing a more robust effect during reinstatement. The locked wheel group allowed an examination of sex differences in heroin reinstatement, which revealed that females showed greater vulnerability to heroin reinstatement than males, but with no other sex differences observed in maintenance or extinction. Overall, the results indicate that voluntary physical exercise may be an effective treatment for heroin dependence in humans.

Sex differences in opioid and psychostimulant craving and relapse: a critical review

“…However, these results are difficult to interpret without ruling out potential confounds related to the oral route of drug administration (i.e., sex differences in pharmacokinetics and taste sensitivity). Smethells et al 124 reported no sex differences in extinction responding but higher heroin priming- and yohimbine-induced reinstatement in females; they also reported higher heroin+cue- and yohimbine+cue-induced reinstatement in females. Vazquez et al 125 reported higher extinction responding and cue-induced reinstatement of heroin seeking in females after limited access continuous drug self-administration in food-restricted rats.…”

Studying Sex Differences in Rodent Models of Addictive Behavior

“…Females also exhibit greater methamphetamine reinstatement than males and require fewer priming injections than males (Reichel et al., 2012; Ruda‐Kucerova et al., 2015). Additionally, female rats show greater reinstatement than males when responding for heroin (Smethells, Greer, Dougen, & Carroll, 2020), EtOH (Bertholomey, Nagarajan, & Torregrossa, 2016), or cannabinoids (Fattore, Spano, Altea, Fadda, & Fratta, 2010). These types of studies suggest a biological influence of sex on relapse‐like behavior.…”

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 ).…”