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.
Highlights
Methamphetamine (METH) addiction is a serious psychosocial problem, which leads to organic harm of the body as well as distortion of the normal functioning of affected people within the society and family
Female rats displayed higher increase of locomotor activity, which lasted for longer time and had higher scores of stereotypies than male rats [28]. These results indicate the sex differences may depend, besides hormonal influences, on different pharmacokinetic processes in females [29]
Horizontal and vertical locomotor activity was measured and a proportion of each in the inner zone of the arena was calculated in order to evaluate differences in the status of anxiety in male and female rats
Summary
Methamphetamine (METH) addiction is a serious psychosocial problem, which leads to organic harm of the body as well as distortion of the normal functioning of affected people within the society and family. Despite the absolute number of female METH abusers being lower than the male ones, women usually appear more dependent, show higher escalation rates [1, 2] and most importantly tend to experience more frequent relapses [3, 4] These gender specific differences require specific treatment strategies for men and women [5,6,7]. After reaching a specific extinction criteria (number of active/inactive responses lower than a set number), one last session is conducted and the reinstatement of the drug-seeking behavior is primed by an environmental factor (stress, cues) or a drug dose Such studies have repeatedly shown female rats to be more vulnerable to drug-primed relapse of METH seeking behavior at conditions of time limited sessions (2 h), which mimic rather consummatory behavior, as well as prolonged self-administration sessions. Analogous results were reported in studies with cocaine [11, 12] and fentanyl [13]
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