Sex Differences and Effects of Modafinil and Allopregnanolone on a Rat Model of Methamphetamine Relapse

Abstract

Modafinil (MOD) is an analeptic drug currently being examined as a treatment for stimulant dependence. This experiment examined MOD’s potential for use in treatment of methamphetamine (METH) addiction and further investigated the role of sex differences in drug-seeking behavior and treatment receptivity. The effects of allopregnanolone (ALLO), a progesterone metabolite that has been previously shown to reduce drug-seeking behavior in female rats, were also examined. Rats were trained to self-administer IV injections of METH during daily 5-hr sessions, and continued stable METH-seeking behavior over a 10 day maintenance period. Next, METH was replaced with saline, and drug-seeking behavior extinguished over an 18-day period. Following extinction, rats began a reinstatement procedure lasting 9 days in which an ALLO, MOD, or control pre-treatment injection was given 30 minutes prior to daily session, followed by a METH or saline priming injection that was given at the start of session. This reinstatement phase is considered an animal model of human relapse. Females showed greater responding on the previously METH-paired lever during reinstatement compared to males. MOD attenuated METH-seeking behavior equally in males and females, while MOD priming injections did not increase responding compared to saline control. ALLO attenuated METH-seeking behavior in females, but had no effect on males. These results illustrate the potential utility of MOD as a treatment for METH addiction and illustrate the role of gonadal hormones, such as ALLO, in the sex differences observed in drug-seeking behavior.