Psychology Department, Ann Arbor MI, 48109 USA; Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA.
Michigan Neuroscience Institute, University of Michigan, Ann Arbor MI, 48109 USA.
Neuropharmacology. 2021 Apr 1;187:108491. doi: 10.1016/j.neuropharm.2021.108491. Epub 2021 Feb 7.
This article reviews evidence for sex differences in vulnerability to addiction with an emphasis on the neural mechanisms underlying these differences. Sex differences in the way that the gonadal hormone, estradiol, interacts with the ascending telencephalic dopamine system results in sex differences in motivated behaviors, including drug-seeking. In rodents, repeated psychostimulant exposure enhances incentive sensitization to a greater extent in females than males. Estradiol increases females' motivation to attain psychostimulants and enhances the value of drug related cues, which ultimately increases their susceptibility towards spontaneous relapse. This, along with females' dampened ability to alter decisions regarding risky behaviors, enhances their vulnerability for escalation of drug use. In males, recent evidence suggests that estradiol may be protective against susceptibility towards drug-preference. Sex differences in the actions of estradiol are reviewed to provide a foundation for understanding how future research might enhance understanding of the mechanisms of sex differences in addiction-related behaviors, which are dependent on estradiol receptor (ER) subtype and the region of the brain they are acting in. A comprehensive review of the distribution of ERα, ERβ, and GPER1 throughout the rodent brain are provided along with a discussion of the possible ways in which these patterns differentially regulate drug-taking between the sexes. The article concludes with a brief discussion of the actions of gonadal hormones on the circuitry of the stress system, including the hypothalamic pituitary adrenal axis and regulation of corticotropin-releasing factor. Sex differences in the stress system can also contribute to females' enhanced vulnerability towards addiction.
本文综述了易感性方面的性别差异的证据，重点是这些差异的神经机制。性腺激素雌激素与上行端脑多巴胺系统相互作用的方式存在性别差异，导致动机行为（包括觅药行为）存在性别差异。在啮齿动物中，重复使用精神兴奋剂会在雌性动物中引起更大程度的激励敏感化，而在雄性动物中则不然。雌激素增加了雌性获得精神兴奋剂的动机，并增强了与药物相关的线索的价值，这最终增加了她们对自发复吸的易感性。再加上女性改变关于冒险行为的决策的能力减弱，这增加了她们对药物使用升级的脆弱性。在男性中，最近的证据表明，雌激素可能对药物偏好的易感性具有保护作用。本文综述了雌激素的作用的性别差异，为理解未来的研究如何增强对与成瘾相关的行为的性别差异机制的理解提供了基础，这些机制取决于雌激素受体（ER）亚型和它们作用的大脑区域。本文还全面综述了 ERα、ERβ 和 GPER1 在啮齿动物大脑中的分布，并讨论了这些模式如何以不同的方式调节性别间的药物摄取。文章最后简要讨论了性腺激素对应激系统回路的作用，包括下丘脑-垂体-肾上腺轴和促皮质素释放因子的调节。应激系统的性别差异也可能导致女性对成瘾的易感性增强。
