Sex-specific Alterations in the mRNA Expression of Histone Deacetylases (HDACs) in the Rat Brain Following Prolonged Abstinence from Methamphetamine Self-administration

Methamphetamine (METH) use disorder (MUD) is a psychiatric disease that imposes substantial health burdens throughout the world. Significant sex-specific differences in misuse and relapse rates exist among human METH users and in preclinical models of MUD. We have been using a METH self-administration (SA) model to identify molecular substrates of sex-related behavioral manifestations. Rats were trained to self-administer METH (0.1 mg/kg/injection, i.v.) over 20 days. Hippocampus (HIP), prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (dSTR) were dissected and used to measure mRNA expression of HDACs because of their potential involvement in MUD. Compared to females, males self-administered more METH. Quantitative PCR revealed that control male rats had higher basal Hdac4 mRNA levels in their HIP and Hdac10 in the PFC in comparison to female controls. In contrast, female controls had higher basal levels of Hdac1, Hdac2, Hdac5, Hdac6, Hdac7, Hdac8, Sirt1, and Sirt2 mRNAs in the PFC. In addition, female METH takers showed decreased mRNA levels of Hdac1, Hdac2, Hdac3, Hdac4, Hdac5, Hdac6, Hdac7, Hdac8 and Hdac11 in their PFC when compared to female controls. Male METH rats had increased Hdac1, Hdac2, Hdac6, Sirt1, and Sirt2 mRNA levels in their PFC, but decreased Hdac4, Sirt4 and Sirt5 mRNA levels in HIP when compared to male controls. These results provide further evidence for sexual dimorphic responses to METH after a long withdrawal interval. These observations support the notion that sex-specific therapeutic approaches using epigenetic agents may be necessary against METH use disorder.