Rudzinskas Sarah A, Mong Jessica A
Program in Neuroscience, University of Maryland, Baltimore, School of Medicine, Baltimore, MD, 21201, United States; Department of Pharmacology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD, 21201, United States.
Program in Neuroscience, University of Maryland, Baltimore, School of Medicine, Baltimore, MD, 21201, United States; Department of Pharmacology, University of Maryland, Baltimore, School of Medicine, Baltimore, MD, 21201, United States.
Neurosci Lett. 2018 Sep 14;683:125-130. doi: 10.1016/j.neulet.2018.06.042. Epub 2018 Jun 23.
Methamphetamine (Meth) is a psychomotor stimulant associated with increased sexual drive and risky sexual behaviors in both men and women. Females are comparatively understudied, despite the fact that are just as likely as men to use methamphetamine. Importantly, Meth-associated sexual behaviors put female-users at a greater risk for unplanned pregnancies, and increase the risk of psychiatric co-morbidities such as depression. Our work in a rodent model has demonstrated that in the presence of the ovarian steroids, estradiol (EB) and progesterone (P), methamphetamine facilitates the activation of neurons of in the Medial Amygdala (MePD) and Ventromedial Nucleus of the Hypothalamus (VMN), nuclei that are integral to female sexual behavior. As methamphetamine has been previously associated with epigenetic changes in males, we hypothesized that methamphetamine may facilitate sexual motivation in females by modulating the amount of epigenetic enzymatic activity in the VMN and MePD. To test this hypothesis, histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activity was quantitated in both the VMN and MePD in the presence and absence of methamphetamine in femalerats who were ovariectomized (OVX), or OVXed and hormone replaced with EB + P. DMNT1 and DNMT3B protein levels were also assessed. Our results show that methamphetamine alters DNMT and HDAC activity in the MePD in an ovarian steroid-dependent fashion. Both methamphetamine alone and EB + P alone significantly reduce DNMT enzymatic activity in an OVX female, but do not further decrease activity when both are given in combination. In contrast, no changes in HDAC or DNMT activity were seen in the VMN regardless of treatment, but the amount of DNMT3b after methamphetamine was significantly altered depending on the presence or absence of ovarian steroids. Taken together, these results support the hypothesis that methamphetamine induces change on an epigenetic level in female rats in both a hormone and nucleus dependent manner, and suggests epigenetic changes may play a role in methamphetamine's mechanism to facilitate the sexual motivation.
甲基苯丙胺（冰毒）是一种精神运动兴奋剂，与男性和女性的性欲增强及危险性行为有关。尽管女性使用甲基苯丙胺的可能性与男性相同，但对女性的相关研究相对较少。重要的是，与甲基苯丙胺相关的性行为使女性使用者面临意外怀孕的更大风险，并增加了诸如抑郁症等精神共病的风险。我们在啮齿动物模型中的研究表明，在存在卵巢类固醇雌二醇（EB）和孕酮（P）的情况下，甲基苯丙胺促进了内侧杏仁核（MePD）和下丘脑腹内侧核（VMN）中神经元的激活，这两个核对于雌性性行为至关重要。由于甲基苯丙胺此前已与男性的表观遗传变化相关联，我们推测甲基苯丙胺可能通过调节VMN和MePD中表观遗传酶活性的量来促进雌性的性动机。为了验证这一假设，我们对去卵巢（OVX）或OVX并用EB + P进行激素替代的雌性大鼠在有或没有甲基苯丙胺的情况下，对VMN和MePD中的组蛋白脱乙酰酶（HDAC）和DNA甲基转移酶（DNMT）活性进行了定量。还评估了DMNT1和DNMT3B蛋白水平。我们的结果表明，甲基苯丙胺以卵巢类固醇依赖性方式改变MePD中的DNMT和HDAC活性。单独使用甲基苯丙胺和单独使用EB + P均可显著降低OVX雌性大鼠的DNMT酶活性，但两者联合使用时不会进一步降低活性。相比之下，无论治疗如何，VMN中均未观察到HDAC或DNMT活性的变化，但甲基苯丙胺处理后DNMT3b的量根据卵巢类固醇的存在与否而显著改变。综上所述，这些结果支持了以下假设：甲基苯丙胺以激素和核依赖性方式在雌性大鼠的表观遗传水平上诱导变化，并表明表观遗传变化可能在甲基苯丙胺促进性动机的机制中起作用。
