Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX 76019, USA.
Department of Psychology, College of Science, The University of Texas at Arlington, Arlington, TX 76019, USA.
Pharmacol Biochem Behav. 2023 Nov;232:173653. doi: 10.1016/j.pbb.2023.173653. Epub 2023 Oct 5.
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.
女性会迅速从消遣性使用可卡因发展为依赖，消耗更多的可卡因，体验到更多可卡因的积极主观影响，并在戒断期间有更高的复发率。这些影响在可卡因成瘾的动物模型中得到了复制，表明女性对可卡因成瘾的敏感性更高，因此更容易受到影响。此外，已经证明雌激素（E2）是女性和雌性动物中可卡因上述影响的关键介质。然而，缺乏确定 E2 对可卡因相关奖励及其潜在神经生物学机制的影响的研究。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。我们表明，E2 通过增强可卡因-环境关联来介导可卡因条件性奖励。此外，E2 介导的可卡因诱导的 CPP 增加与伏隔核、背侧纹状体和腹侧被盖区中 ERK1/2 和 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，我们在可卡因条件作用期间和 CPP 测试之前抑制 ERK1/2 和/或 mTOR 活性。在条件作用期间抑制 ERK1/2 阻断了女性的可卡因-CPP，抑制 mTOR 没有效果，而在 CPP 测试之前抑制 ERK1/2 和 mTOR 阻断了可卡因-CPP。总之，我们已经确定，E2 通过增强可卡因-环境关联的形成来增强可卡因条件性奖励。此外，在可卡因条件作用期间激活 ERK1/2 对于 E2 增强可卡因条件性奖励是必要的。意义声明：描述 E2 在可卡因-环境关联形成过程中作用的分子基础的研究实际上是未知的。在这项研究中，我们确定了 E2 在可卡因-CPP 形成过程中的影响，并在奖励途径的重要节点内描述了 ERK1/2 和 mTOR 活性在这种作用中的作用。阐明 E2 在可卡因诱导的细胞内信号传导中的作用填补了我们关于 E2 如何影响细胞内信号传导途径以指示刺激的动机显著性的知识中的一个重要空白。这些数据对于我们理解波动的激素水平如何使女性对可卡因的奖励作用变得越来越敏感至关重要。
