McCoy Michael T, Daiwile Atul P, Ladenheim Bruce, Cadet Jean Lud
Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, 21224, USA.
Mol Neurobiol. 2025 Mar 28. doi: 10.1007/s12035-025-04869-7.
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.
甲基苯丙胺（METH）使用障碍（MUD）是一种在全球范围内造成重大健康负担的精神疾病。在人类甲基苯丙胺使用者以及MUD的临床前模型中，滥用和复发率存在显著的性别差异。我们一直在使用甲基苯丙胺自我给药（SA）模型来确定与性别相关行为表现的分子底物。大鼠经过20天的训练以自我静脉注射甲基苯丙胺（0.1毫克/千克/注射）。由于海马体（HIP）、前额叶皮质（PFC）、伏隔核（NAc）和背侧纹状体（dSTR）可能与MUD有关，因此将其解剖并用于测量组蛋白去乙酰化酶（HDACs）的mRNA表达。与雌性相比，雄性自我注射的甲基苯丙胺更多。定量PCR显示，与雌性对照相比，对照雄性大鼠海马体中的基础Hdac4 mRNA水平较高，前额叶皮质中的Hdac10较高。相反，雌性对照在前额叶皮质中的Hdac1、Hdac2、Hdac5、Hdac6、Hdac7、Hdac8、沉默信息调节因子1（Sirt1）和沉默信息调节因子2（Sirt2）mRNA基础水平较高。此外，与雌性对照相比，服用甲基苯丙胺的雌性大鼠前额叶皮质中的Hdac1、Hdac2、Hdac3、Hdac4、Hdac5、Hdac6、Hdac7、Hdac8和Hdac11 mRNA水平降低。与雄性对照相比，服用甲基苯丙胺的雄性大鼠前额叶皮质中的Hdac1、Hdac2、Hdac6、Sirt1和Sirt2 mRNA水平升高，但海马体中的Hdac4、Sirt4和Sirt5 mRNA水平降低。这些结果为长时间戒断后对甲基苯丙胺的性别二态性反应提供了进一步证据。这些观察结果支持这样一种观点，即使用表观遗传药物的性别特异性治疗方法可能对甲基苯丙胺使用障碍是必要的。
