Sex Differences in the Mechanisms that Promote Nicotine Reward and Withdrawal

说明(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，特别是在比男性更容易受到吸烟长期健康后果影响的女性中。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性的知识差距。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仍将在很大程度上令人费解。我们研究计划的长期目标是确定在不同的临床人群中调节烟草使用的机制，这些人群对这个问题特别敏感。这样做的目的是 更新换代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，戒烟后产生的焦虑加剧。我们的机制假设是，雌二醇(E2)促进了尼古丁的奖赏效应，并放大了女性戒烟产生的压力。更具体地说，我们假设对尼古丁的反应的性别差异是在伏核(NAcc)的神经回路中调节的，在那里，多巴胺在尼古丁注射后增加，在停药期间减少。因此，女性在存在促进NAcc中多巴胺释放的E2时，会体验到尼古丁的更大回报效应。在反复接触尼古丁之后，对抗过程的发展是为了抵消多巴胺释放的长期过度激活。我们认为，在慢性尼古丁戒断过程中，随着NAcc中应激激素促肾上腺皮质激素释放因子(CRF)的增加，这些对立过程的出现是明显的。CRF水平的增加增强了NAcc的抑制性基调，导致尼古丁戒断过程中多巴胺释放减少。因此，在E2存在的情况下，女性在尼古丁戒断过程中体验到更大的焦虑，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(目标1)和戒烟产生的厌恶状态(目标2)的性别差异，因为这两个因素都被认为促进了女性的烟草使用。研究性别差异的方法包括比较雄性、雌性和OVX雌性大鼠。如果卵巢激素的去除逆转了女性的拟议措施，那么将在将接受E2补充的OVX大鼠中评估E2的作用，并将在服用E2或赋形剂后进行测试。在这个项目完成后，我们的发现将帮助我们开发一个关于促进女性吸烟的因素的统一假说。这说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.