RNA sequencing analysis identifies sex differences in transcriptional signatures in the dorsal striatum of female and male rats after withdrawal from methamphetamine self-administration

Significant methamphetamine (METH)-induced behavioral differences exist between the two sexes of humans and other animals. These dissimilarities may be related to sexual dimorphism in baseline molecular and biochemical mechanisms in brain reward neuroanatomical pathways. As a first step towards identifying sex-based differences in methamphetamine-induced transcriptional signatures, we used RNA sequencing analysis to measure genome-wide changes in gene expression in the dorsal striatum of rats that had self-administered METH. We trained rats to self-administer METH (0.1 mg/kg/infusion, i.v.) using two 3-hr daily sessions (with 30 min time out between sessions) for 20 days. Control rats self-administered saline under similar conditions. This was followed by drug seeking tests on withdrawal days 3 (WD3) and 30 (WD30). Behavioral results show that male rats took more METH than female rats. In both male and female rats, some animals escalated (high-takers) whereas others did not escalate (low-takers) their METH intake during the behavioral experiment. Rats were euthanized 24 h after the second drug seeking test. RNA was extracted from the dorsal striatum (dSTR) and used in RNA sequencing analysis. The data identified substantial baseline differences in gene expression between female and male control rats. In addition, METH use and withdrawal were associated with significant sex-related differences in changes in striatal gene expression, with minimal overlaps of altered mRNAs. Thus, the present results provide further supporting evidence for sexually dimorphic responses to METH exposure. These observations support the notion of sex-specific approaches to the treatment of patients who suffer from METH use disorder.