Neuroinflammatory and glutamatergic mechanisms of nicotine seeking

项目总结/摘要 尼古丁的使用是公共卫生的一个重大负担。此外，渴望和复吸似乎各不相同， 女性的性别和月经周期阶段的功能，从而增加17β-雌二醇（E2）和 孕酮（P4）分别与成瘾易感性和恢复力相关。P4已检查 临床上作为戒烟剂，似乎对妇女有希望。然而，研究表明， 在男性中显示出不明确或有限的功效。其衍生物别孕烯醇酮（allopregnanolone，ALLO）最近被 美国食品和药物管理局（FDA）批准将其作为产后抑郁症的治疗药物，尽管它没有 被批准为戒烟药物。在临床前研究中，激素与尼古丁神经生物学相互作用， 性的功能。我们已经发现，神经免疫信号的核心，一个关键的大脑 与药物奖励相关的区域，是由尼古丁寻求和消费以性别特异性的方式驱动的， 雌性大鼠更容易受到尼古丁使用引起的神经免疫后果的影响， 对雄性来说具体来说，我们已经表明，NAcore小胶质细胞在女性中比在男性中更容易被尼古丁激活。 男性。此外，我们已经证明，核因子-κ B（NF-κB）通路的激活发生在 尼古丁自我给药（SA），并且有必要抑制以减少其他药物治疗 寻找尼古丁我们还表明，尼古丁需求强度（通过行为经济学测量） 对合成激素和卵巢激素敏感在这份多样性补充报告中，肯德里克先生将揭露 奖励途径中的神经免疫信号传导对治疗效果的潜在关键贡献 P4和ALLO作为减少尼古丁消耗的性别函数。我们将测试这些化合物的必要性 抑制NAcore内的神经免疫激活，以发挥减少尼古丁的治疗作用 消费在目标1中，我们将测试抑制NAcore NF-κB信号传导是否是P4和ALLO 降低尼古丁需求强度。我们假设这在女性中是正确的，但在男性中不是。在目标2中， 将建立必要的条件关系，通过双向化学遗传操纵， 在尼古丁SA期间长期施用P4、ALLO或媒介物的同时，我们假设P4和 ALLO将减少尼古丁的消耗和小胶质细胞的激活，但小胶质细胞的化学激活 将消除这种影响。我们进一步假设，这将只在女性中明显。这些研究一起 将是第一个建立NAcore神经免疫抑制（通过NF-κB和小胶质细胞活化）的必要性， 两种潜在的基于类固醇的药物疗法对两种性别戒烟的疗效。这将 也是第一组研究，以确定ALLO是否显示出临床前疗效，在减少尼古丁的需求， 男女都有。这一系列的研究有可能通过以下方式指导促进戒烟的策略： 发现新的神经机制，并可能证明检查其他可能的治疗方法，具有抗- 戒烟的炎症特性，这可能会在两种性别中产生更高的疗效。

PROJECT SUMMARY/ABSTRACT Nicotine use is a substantial burden to public health. Further, craving and relapse to smoking appear to vary as a function of sex and of menstrual cycle phase in women, whereby increases in 17β-estradiol (E2) and progesterone (P4) are associated with addiction vulnerability and resilience, respectively. P4 has been examined clinically as a smoking cessation agent and appears to show promise for women. However, studies incorporating men have shown unclear or limited efficacy in men. Its derivative, allopregnanolone (ALLO), was recently approved by the Food and Drug Administration (FDA) as a treatment for post-partum depression, although it not approved as a smoking cessation agent. In preclinical studies, hormones interact with nicotine neurobiology as a function of sex. We have found that neuroimmune signaling within the nucleus accumbens core, a key brain region associated with drug reward, is driven by nicotine seeking and consumption in a sex-specific fashion, whereby female rats are more susceptible to neuroimmune consequences induced by nicotine use as compared to males. Specifically, we have shown that NAcore microglia are more activated by nicotine in females than in males. Further, we have shown that activation of the nuclear factor-kappa B (NF-κB) pathway occurs following nicotine self-administration (SA), and is necessary to inhibit in order for other pharmacotherapies to reduce nicotine seeking. We have also shown that nicotine demand intensity (as measured via behavioral economics) is sensitive to synthetic and ovarian hormones. Under this diversity supplement, Mr. Kendrick will uncover potentially critical contributions of neuroimmune signaling within the reward pathway to the therapeutic effects of P4 and ALLO as a function of sex in reducing nicotine consumption. We will test necessity of these compounds to inhibit neuroimmune activation within the NAcore in order to exert therapeutic effects in reducing nicotine consumption. In Aim 1, we will test if inhibition of NAcore NF-κB signaling is necessary for P4 and ALLO to decrease nicotine demand intensity. We hypothesize that this will be true in females but not males. In Aim 2, we will establish the conditional relationship of necessity through bidirectional chemogenetic manipulation of microglia while chronically administering P4, ALLO, or vehicle during nicotine SA. We hypothesize that P4 and ALLO will reduce nicotine consumption and microglial activation, but that chemogenetic activation of microglia will occlude this effect. We further hypothesize that this will only be evident in females. Together, these studies will be the first to establish necessity of NAcore neuroimmune inhibition (via NF-κB and microglial activation) in the efficacy of two potential steroid-based pharmacotherapies for smoking cessation across both sexes. This will also be the first set of studies to determine if ALLO shows preclinical efficacy in decreasing nicotine demand in both sexes. This line of research has the potential to guide strategies for promoting smoking cessation through discovery of novel neural mechanisms, and may justify examination of other possible therapeutics that have anti- inflammatory properties for smoking cessation which may yield higher efficacy across both sexes.