Women rapidly progress from recreational cocaine use to dependence, consume greater quantities of cocaine, experience more positive subjective effects of cocaine and have higher incidences of relapse during abstinence. These effects have been replicated in animal models of cocaine addiction and indicate an enhanced sensitivity and therefore, vulnerability of females to cocaine addiction. Furthermore, it has been demonstrated that estradiol (E2) is a key mediator of the aforementioned effects of cocaine in women and female animals. However, studies identifying the influence of E2 on cocaine-associated reward and its underlying neurobiological mechanisms are lacking. Here, we further explored the influence of E2 on cocaine conditioned place preference in female rats. We show that E2 mediates cocaine-conditioned reward by potentiating cocaine-context associations. In addition, the E2-mediated increases in cocaine-induced CPP are associated with increased activation of ERK1/2 and mTOR proteins in the nucleus accumbens, dorsal striatum, and ventral tegmental area. To assess the involvement of ERK1/2 and mTOR in E2-mediated enhanced cocaine-CPP, we inhibited ERK1/2 and/or mTOR activity during cocaine-conditioning and before CPP-test. Inhibition of ERK1/2 during conditioning blocked cocaine-CPP in females, inhibition mTOR was without effect, and inhibiting ERK1/2 and mTOR before CPP-test blocked cocaine-CPP. In conclusion, we have established that E2 enhances cocaine-conditioned reward by potentiating cocaine-context associations formed during conditioning. Additionally, activation of ERK1/2 during cocaine-conditioning is necessary for the potentiation of cocaine-conditioned reward by E2.

Significance statement

Studies characterizing the molecular substrates underlying the effects of E2 during the formation of cocaine-context associations are virtually unknown. In this study, we established the influence of E2 during the formation of cocaine-CPP and characterized the role of ERK1/2 and mTOR activity on this effect within significant nodes of the reward pathway. The elucidation of the role of E2 in cocaine-induced intracellular signaling fills a significant gap in our knowledge regarding the mechanisms by which E2 affects intracellular signaling pathways to indicate the motivational salience of a stimulus. These data are crucial to our understanding of how fluctuating hormone levels can render females increasing sensitive to the rewarding effects of cocaine.

中文翻译：

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雌二醇和 ERK 之间的相互作用，但不是 mTOR，信号传导对于增强雌性大鼠可卡因诱导的条件性位置偏好是必要的

女性从娱乐性使用可卡因迅速发展为依赖，消费更多的可卡因，体验到可卡因更积极的主观影响，并且在戒断期间复发的几率更高。这些效应已在可卡因成瘾的动物模型中得到复制，表明女性对可卡因成瘾的敏感性增强，因此更容易受到影响。此外，已经证明雌二醇（E2）是可卡因对女性和雌性动物的上述作用的关键介质。然而，目前尚缺乏确定 E2 对可卡因相关奖赏的影响及其潜在神经生物学机制的研究。在这里，我们进一步探讨了 E2 对雌性大鼠可卡因条件性位置偏好的影响。我们发现 E2 通过增强可卡因-情境关联来介导可卡因条件奖赏。此外，E2介导的可卡因诱导的CPP增加与伏核、背侧纹状体和腹侧被盖区mTOR蛋白的激活增加有关。为了评估 ERK1/2 和 mTOR 在 E2 介导的增强可卡因-CPP 中的参与，我们在可卡因调节期间和 CPP 测试之前抑制 ERK1/2 和/或 mTOR 活性。在调节过程中抑制ERK1/2可阻断女性的可卡因-CPP，抑制mTOR则无效，而在CPP试验前抑制ERK1/2和mTOR可阻断可卡因-CPP。总之，我们确定 E2 通过增强调节过程中形成的可卡因-情境关联来增强可卡因调节奖赏。此外，在可卡因条件作用期间激活 ERK1/2 对于 E2 增强可卡因条件奖励是必要的。

意义陈述

描述可卡因-背景关联形成过程中 E2 影响的分子底物的研究实际上是未知的。在本研究中，我们确定了 E2 在可卡因-CPP 形成过程中的影响，并表征了奖励途径重要节点内 ERK1/2 和 mTOR 活性对此影响的作用。E2 在可卡因诱导的细胞内信号传导中的作用的阐明填补了我们关于 E2 影响细胞内信号传导途径以表明刺激的动机显着性的机制的知识空白。这些数据对于我们了解激素水平的波动如何使女性对可卡因的奖励作用越来越敏感至关重要。