Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, New York 10029, USA.
Department of Pharmacological Sciences, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Nat Commun. 2017 Jan 10;8:13877. doi: 10.1038/ncomms13877.
Although both males and females become addicted to cocaine, females transition to addiction faster and experience greater difficulties remaining abstinent. We demonstrate an oestrous cycle-dependent mechanism controlling increased cocaine reward in females. During oestrus, ventral tegmental area (VTA) dopamine neuron activity is enhanced and drives post translational modifications at the dopamine transporter (DAT) to increase the ability of cocaine to inhibit its function, an effect mediated by estradiol. Female mice conditioned to associate cocaine with contextual cues during oestrus have enhanced mesolimbic responses to these cues in the absence of drug. Using chemogenetic approaches, we increase VTA activity to mechanistically link oestrous cycle-dependent enhancement of VTA firing to enhanced cocaine affinity at DAT and subsequent reward processing. These data have implications for sexual dimorphism in addiction vulnerability and define a mechanism by which cellular activity results in protein alterations that contribute to dysfunctional learning and reward processing.
尽管男性和女性都会对可卡因上瘾，但女性更容易上瘾，并且更难保持戒断状态。我们展示了一种发情周期依赖性机制，该机制控制着女性对可卡因奖赏的增加。在发情期，腹侧被盖区（VTA）多巴胺神经元的活动增强，并促使多巴胺转运体（DAT）发生翻译后修饰，从而增加可卡因抑制其功能的能力，这种作用是由雌二醇介导的。在发情期与环境线索形成可卡因关联的雌性小鼠，在没有药物的情况下，对这些线索的中脑边缘反应增强。使用化学遗传方法，我们增加 VTA 的活动，将发情周期依赖性 VTA 放电增强与 DAT 上可卡因亲和力的增强以及随后的奖励处理联系起来。这些数据对成瘾易感性的性别二态性有影响，并定义了一种机制，即细胞活动导致蛋白质改变，从而导致学习和奖励处理功能障碍。
