Molecular Neuropsychiatry Research Branch, NIDA Intramural Research Program, Baltimore, MD, 21224, USA.
Neurotox Res. 2022 Oct;40(5):1464-1478. doi: 10.1007/s12640-022-00545-z. Epub 2022 Jul 14.
Sex differences have been reported in methamphetamine (METH) use disorder in humans and in animal models of METH exposure. Specifically, animals that self-administer METH show sex-related dissimilarities in dopamine (DA) metabolism. To better understand the molecular bases for the differences in DA metabolism, we measured the levels of mRNAs of enzymes that catalyze DA synthesis and breakdown in the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and hippocampus (HIP) of rats that had self-administered METH. There were significant sex differences in control rats, with males having higher basal levels of Th in the PFC and dSTR, Ddc in the NAc, and MaoB in the HIP. In contrast, female controls showed higher basal levels of Comt in the HIP. Male and female METH SA rats also showed some distinct responses to the drug. Specifically, female METH rats exhibited increased expression of Ddc and MaoB, whereas male METH animals showed higher levels of Comt mRNA in the PFC compared to their respective controls. In the NAc, male METH rats displayed decreased Th and Ddc mRNA levels. Together, our results identified sex-dependent and region-specific changes in the mRNA expression of several enzymes involved in DA synthesis and breakdown in response to METH SA, with the majority of differences being observed in the mesocorticolimbic dopaminergic system. These findings are of significant translational importance providing further support for the inclusion of sex as an important variable when planning and evaluating therapeutic interventions against METH use disorder in human clinical studies.
性别差异已在人类甲基苯丙胺（METH）使用障碍和 METH 暴露的动物模型中得到报道。具体来说，自我给予 METH 的动物在多巴胺（DA）代谢方面表现出与性别相关的差异。为了更好地理解 DA 代谢差异的分子基础，我们测量了自我给予 METH 的大鼠前额叶皮层（PFC）、伏隔核（NAc）、背侧纹状体（dSTR）和海马（HIP）中催化 DA 合成和分解的酶的 mRNA 水平。在对照大鼠中存在显著的性别差异，雄性大鼠在 PFC 和 dSTR 中的 Th、NAc 中的 Ddc 和 HIP 中的 MaoB 基础水平较高。相比之下，雌性对照大鼠 HIP 中的 Comt 基础水平较高。雄性和雌性 METH SA 大鼠对药物也表现出一些明显的反应。具体来说，雌性 METH 大鼠表现出 Ddc 和 MaoB 的表达增加，而雄性 METH 动物与各自的对照相比，在 PFC 中显示出更高水平的 Comt mRNA。在 NAc 中，雄性 METH 大鼠的 Th 和 Ddc mRNA 水平降低。总的来说，我们的研究结果确定了几种参与 DA 合成和分解的酶的 mRNA 表达在性别依赖性和区域特异性方面对 METH SA 的反应发生变化，大多数差异在中边缘多巴胺能系统中观察到。这些发现具有重要的转化意义，为在人类临床研究中规划和评估针对 METH 使用障碍的治疗干预措施时将性别作为一个重要变量提供了进一步的支持。
