Dopaminergic dynamics underlying sex-specific cocaine reward.
Dopaminergic dynamics underlying sex-specific cocaine reward.
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DOI：
10.1038/ncomms13877
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发表时间：
2017-01-10
影响因子：
16.6
通讯作者：
Nestler EJ
中科院分区：
文献类型：
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作者：
Calipari ES;Juarez B;Morel C;Walker DM;Cahill ME;Ribeiro E;Roman-Ortiz C;Ramakrishnan C;Deisseroth K;Han MH;Nestler EJ
虽然男性和女性都对可卡因上瘾，但女性更快地过渡到上瘾，并且更难保持戒断。我们证明了一个发情周期依赖的机制控制增加可卡因奖励的女性。在发情期间，腹侧被盖区（VTA）多巴胺神经元活性增强，并驱动多巴胺转运蛋白（DAT）的翻译后修饰，以增加可卡因抑制其功能的能力，这是雌二醇介导的作用。雌性小鼠在动情期习惯于将可卡因与情境线索联系起来，在没有药物的情况下，它们对这些线索的中边缘反应增强。使用化学发生学方法，我们增加VTA活性，以机械地将发情周期依赖的VTA放电增强与DAT和随后的奖励处理的可卡因亲和力增强联系起来。这些数据对成瘾脆弱性的性二态性有影响，并定义了一种机制，通过这种机制，细胞活动导致蛋白质改变，导致功能失调的学习和奖励处理。目前，人们对奖赏加工的性别差异知之甚少。Calipari和Juarez等人报道了腹侧被盖区多巴胺神经元放电的发情周期依赖性波动，其驱动NAc终末中表达的DAT功能的改变。这些差异是发情期可卡因奖赏加工增强的基础。
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. Sex differences in reward processing are at present poorly understood. Calipari and Juarez et al. report oestrous cycle-dependent fluctuations in firing of VTA dopamine neurons that drive alterations in DAT function expressed in terminals in the NAc. These differences underlie enhanced cocaine reward processing during oestrus.