Sex Differences in the Mechanisms that Promote Nicotine Reward and Withdrawal

描述（由申请人提供）：烟草使用仍然是一个主要的公共卫生和经济问题，特别是对于女性来说，她们比男性更容易受到吸烟造成的长期健康后果。尽管问题很严重，但我们对促进女性吸烟的机制的理解仍存在基本知识差距。如果这一知识空白得不到填补，那么减少烟草使用和为女性吸烟者开发专门药物将在很大程度上令人难以理解。我们研究计划的长期目标是确定在特别容易受到此问题影响的不同临床人群中介导烟草使用的机制。此举的目的 更新的目的是确定促进女性吸烟的神经机制。核心假设是，女性比男性更容易受到烟草使用的影响，因为尼古丁的奖赏效应更强，并且戒断这种药物会加剧焦虑。我们的机制假设是，雌二醇 (E2) 会促进尼古丁的奖励作用，并放大女性因尼古丁戒断而产生的压力。更具体地说，我们假设对尼古丁反应的性别差异是在伏隔核（NAcc）的神经回路内调节的，其中多巴胺在尼古丁给药后增加，在戒断药物期间减少。因此，在 E2 存在的情况下，女性会体验到更大的尼古丁奖励效应，E2 会促进 NAcc 中多巴胺的释放。反复接触尼古丁后，对抗过程会发展以抵消多巴胺释放的慢性过度激活。我们认为，在戒除慢性尼古丁期间，随着 NAcc 中应激激素、促肾上腺皮质激素释放因子 (CRF) 的增加，这些对抗过程的出现是明显的。 CRF 水平的增加增强了 NAcc 中的抑制音，从而导致尼古丁戒断期间多巴胺释放减少。因此，在 E2 存在的情况下，女性在尼古丁戒断过程中会经历更大的焦虑，这会促进抑制 NAcc 中多巴胺释放的对手应激系统的募集。拟议的研究反映了一种涉及神经化学、行为和基因转移技术的多学科方法，以比较尼古丁的奖励作用（目标 1）和戒断产生的厌恶状态（目标 2）的性别差异，因为这两个因素被认为会促进女性吸烟。研究性别差异的方法包括对雄性、雌性和 OVX 雌性大鼠进行比较。如果去除卵巢激素逆转了雌性中建议的措施，则将在接受 E2 补充的 OVX 大鼠中评估 E2 的作用，并在 E2 或载体给药后进行测试。该项目完成后，我们的研究结果将帮助我们就促进女性吸烟的因素制定一个统一的假设。这说明了这项研究的重要性，因为更好地了解促进女性吸烟的机制将有助于找到更有效的治疗方法，以减少女性的健康差距。

DESCRIPTION (provided by applicant): Tobacco use remains a major public health and economic concern, particularly in women who are more vulnerable to the long-term health consequences of smoking than men. Despite the magnitude of the problem, there is a fundamental knowledge gap in our understanding of the mechanisms that promote tobacco use in females. If this knowledge gap is not filled, then reducing tobacco use and developing specialized medications for female smokers will remain largely incomprehensible. The long-term goal of our research program is to identify the mechanisms that mediate tobacco use among different clinical populations that are uniquely susceptible to this problem. The objective of this renewal is to determine the neural mechanisms that promote tobacco use in females. The central hypothesis is that females are more susceptible to tobacco use than males because of stronger rewarding effects of nicotine and heightened anxiety produced by withdrawal from this drug. Our mechanistic hypothesis is that estradiol (E2) promotes the rewarding effects of nicotine and magnifies the stress produced by nicotine withdrawal in females. More specifically, we postulate that sex differences in response to nicotine are modulated within the neural circuits of the nucleus accumbens (NAcc), where dopamine is increased following nicotine administration and decreased during withdrawal from this drug. Thus, females experience greater rewarding effects of nicotine in the presence of E2, which promotes dopamine release in the NAcc. Following repeated nicotine exposure, opponent processes develop to counteract the chronic over-activation of dopamine release. We suggest that the emergence of these opponent processes is evident during withdrawal from chronic nicotine as an increase in the stress hormone, corticotropin releasing factor (CRF) in the NAcc. This increase in CRF levels enhances the inhibitory tone in the NAcc, which results in a decrease in dopamine release during nicotine withdrawal. Thus, females experience greater anxiety during nicotine withdrawal in the presence of E2, which promotes the recruitment of opponent stress systems that suppress dopamine release in the NAcc. The proposed studies reflect a multi- disciplinary approach involving neurochemical, behavioral, and gene transfer techniques to compare sex differences in the rewarding effects of nicotine (Aim 1) and the aversive states produced by withdrawal (Aim 2) because both of these factors are believed to promote tobacco use in females. The approach to studying sex differences involves comparisons of male, female, and OVX female rats. If the removal of ovarian hormones reverses the proposed measures in females, then the role of E2 will be assessed in OVX rats that will receive E2 supplementation and will be tested following E2 or vehicle administration. At the completion of this project, our findings will help us develop a unifying hypothesis regarding the factors that promote tobacco use in females. This exemplifies the significance of this research because a better understanding of the mechanisms that fuel tobacco use in females will lead to more effective treatments to reduce health disparities in women.