Sex differences in escalated methamphetamine self-administration and altered gene expression associated with incubation of methamphetamine seeking.

Abstract

BACKGROUND Methamphetamine (METH) use disorder (MUD) is prevalent worldwide. There are reports ofsex differences in quantities of drug used and relapses to drug use among individuals with MUD. However, the molecular neurobiology of these potential sex differences remains unknown. METHODS We trained rats to self-administer METH (0. 1 mg/kg/infusion, IV) on a FR-1 schedule for 20 days using two 3-h daily METH sessions separated by 30 min breaks. At the end of self-administration (SA) training, rats underwent tests of cue-induced METH seeking on withdrawal days 3 (WD3) and 30 (WD30). Twenty-four hours later, nucleus accumbens (NAc) was dissected and then used to measure neuropeptide mRNA levels. RESULTS Behavioral results show that male rats increased the number of METH infusions earlier during SA training and took more METH than females. Both male and female rats could be further divided into two phenotypes labeled high and low takers based on the degree of escalation that they exhibited during the course of the METH SA experiment. Both males and females exhibited incubation of METH seeking after 30 days of forced withdrawal. Females had higher basal mRNA levels of dynorphin (Pdyn) and hypocretin/orexin receptors (Hcrtr1/2) than males whereas males expressed higher vasopressin mRNA levels than females under saline and METH conditions. Unexpectedly, only males showed increased expression of NAc dynorphin after METH SA. Moreover, there were significant correlations between NAc Hcrtr1, Hcrtr2, Crhr2, and Avpr1b mRNA levels and cue-induced METH seeking only in female rats. CONCLUSION Our results identify some behavioral and molecular differences between male and female rats that had self-administered METH. Sexual dimorphism in responses to METH exposure should be considered when developing potential therapeutic agents against METH use disorder.