Sex Differences in the Reinstatement of Methamphetamine Seeking after Forced Abstinence in Sprague-Dawley Rats

Abstract

Preventing relapse to drug abuse is one of the struggles faced by clinicians in order to treat patients with substance use disorders (DSM-5). There is a large body of clinical evidence suggesting differential characteristics of the disorder in men and women, which is in line with preclinical findings as well. The aim of this study was to assess differences in relapse-like behavior in methamphetamine (METH) seeking after a period of forced abstinence, which simulates the real clinical situation very well. Findings from such study might add new insights in gender differences in relapse mechanisms to previous studies, which employ a classical drug or cue-induced reinstatement procedure following the extinction training. Adult male and female Sprague-Dawley rats were used in IV self-administration procedure conducted in operant boxes using nose-poke operandi (Coulborn Instruments, USA). Active nose-poke resulted in activation of the infusion pump to deliver one intravenous infusion of METH (0.08 mg/kg). After baseline drug intake was established (maintenance phase), a period of forced abstinence was initiated and rats were kept singly in their home cages for 14 days. Finally, one reinstatement session in operant boxes was conducted. Females were found to self-administer significantly lower dose of METH. The relapse rate was assessed as a number of active nose-pokes during the reinstatement session, expressed as a percentage of active nose-poking during the maintenance phase. Females displayed approximately 300% of active nose-pokes compared to 50% in males. This indicates higher vulnerability to relapse of METH seeking behavior in female rats. This effect was detected in all females, independently of current phase of their estrous cycle. Therefore, this paradigm using operant drug self-administration and reinstatement of drug-seeking after forced abstinence model can be used for preclinical screening for potential new anti-relapse medications specific for women.

Methamphetamine: Effects on the brain, gut and immune system

“…METH has more potent effects in women than men. In fact, 6-fold greater vulnerability to relapse of METH-seeking behavior is evident in experimental female rats as compared to male rats (15). Changes in brain morphology, such as hippocampus volume reduction, were seen in METHabstinent females but not in males (16).…”

Sex differences in the acute locomotor response to methamphetamine in BALB/c mice

“…As in humans, rats exhibit sex-dependent responses in that females are more sensitive to its acute locomotor activating effects[5], self-administer more METH than males [6] and are more likely to reinstate METH-seeking behavior following periods of abstinence [7]. Additionally, neonatal METH exposure results in sex-dependent differences on memory tasks [8] and striatal protein kinase A activity [9] in adult rats.…”

Sex Differences in Context-Driven Reinstatement of Methamphetamine Seeking Is Associated with Distinct Neuroadaptations in the Dentate Gyrus<strong> </strong>

“…Previous studies have examined sex differences in animal models of methamphetamine addiction and have focused on differences during selfadministration, extinction and drug-or cue-induced reinstatement of methamphetamine seeking (Roth & Carroll, 2004;Holtz et al, 2012;Reichel et al, 2012;Ruda-Kucerova et al, 2015;Bernheim et al, 2017;Cox et al, 2017;Pittenger et al, 2017;Weber et al, 2018). The current study examined whether sex differences occur during context-driven reinstatement of extinguished methamphetamine-seeking behavior following prolonged abstinence from methamphetamine self-administration.…”