Sex Differences in the Mechanisms that Promote Nicotine Reward and Withdrawal

烟草使用仍然是一个主要的公共卫生和经济问题，特别是在女性中，她们比男性更容易受到吸烟的长期健康后果的影响。尽管这个问题很严重，但在我们对促进女性吸烟的机制的理解方面存在着根本的知识差距。如果不填补这一知识空白，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仍然难以理解。我们研究计划的长期目标是确定介导不同临床人群中烟草使用的机制，这些人群特别容易受到这个问题的影响。的目的 更新是为了确定促进女性吸烟的神经机制。中心假设是，女性比男性更容易受到烟草使用的影响，因为尼古丁的奖励作用更强，戒断这种药物会产生更大的焦虑。我们的机制假设是，雌二醇（E2）促进尼古丁的奖励作用，并放大尼古丁戒断所产生的压力在女性。更具体地说，我们假设对尼古丁反应的性别差异在丘脑核（NAcc）的神经回路内受到调制，其中多巴胺在尼古丁给药后增加，在戒断过程中减少。因此，女性在E2的存在下体验到尼古丁的更大奖励作用，这促进了NAcc中的多巴胺释放。在反复暴露于尼古丁之后，对抗过程发展以抵消多巴胺释放的慢性过度激活。我们认为，这些对手过程的出现是显而易见的，在退出慢性尼古丁的应激激素，促肾上腺皮质激素释放因子（CRF）在NAcc的增加。CRF水平的这种增加增强了NAcc中的抑制性张力，这导致尼古丁戒断期间多巴胺释放减少。因此，女性在尼古丁戒断期间在E2的存在下经历更大的焦虑，这促进了抑制NAcc中多巴胺释放的对手应激系统的招募。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效应（目的1）和戒断产生的厌恶状态（目的2）的性别差异，因为这两个因素被认为会促进女性的烟草使用。研究性别差异的方法包括比较雄性、雌性和OVX雌性大鼠。如果去除卵巢激素逆转了雌性动物的拟定措施，则将在接受E2补充的OVX大鼠中评估E2的作用，并在E2或溶媒给药后进行检测。在这个项目完成后，我们的研究结果将帮助我们制定一个统一的假设，促进女性吸烟的因素。这证明了这项研究的重要性，因为更好地了解女性吸烟的机制将导致更有效的治疗，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.