Influence of the natural hormonal milieu on perfusion fMRI smoking cue responses

自然激素环境对灌注 fMRI 吸烟提示反应的影响

• 批准号: 9893853
• 负责人: Reagan R Wetherill
• 金额: $ 39.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893853
• 关键词: Address; Affect; Affective; American; Animal Model; Animals; Attention; Behavior; Behavioral; Brain; Chronic; Clinical Management; Code; Corpus striatum structure; Cues; Desire for food; Dopamine; Estradiol; Exhibits; Female; Functional Magnetic Resonance Imaging; Genes; Genotype; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormonal; Human; Image; Individual; Insula of Reil; Intervention; Knowledge; Laboratories; Link; Literature; Luteal Phase; Measures; Medial; Menstrual cycle; Minisatellite Repeats; Nicotine; Perfusion; Pharmaceutical Preparations; Progesterone; Public Health; Relapse; Research; Research Design; Rewards; Savings; Smoke; Smoker; Smoking; System; Time; Untranslated Regions; Woman; attentional bias; behavioral response; cigarette smoking; clinically relevant; cohort; cue reactivity; design; dopamine transporter; drug seeking behavior; improved; men; neurobehavioral; neuroimaging; novel; preventable death; programs; proliferative phase Menstrual cycle; protective effect; relating to nervous system; response; smoking cessation; smoking cue; success; treatment strategy; uptake

Cigarette smoking is the number one cause of preventable death in the U.S. however, despite the known health consequences of smoking, 1 in 5 Americans continues to smoke. Most smokers desire to quit but success rates are low. Women have greater difficulty quitting smoking and suffer greater smoking-related health consequences than men. Greater knowledge of relapse vulnerabilities in women could help to identify treatment targets and result in interventions that improve health and save lives. The guiding hypothesis for this proposal is that fluctuations in gonadal sex hormones [estradiol (E) and progesterone (P)] over the course of the menstrual cycle (MC) may greatly impact relapse vulnerability through their actions on a powerful relapse motivator, smoking-related cue (SC) exposure. This hypothesis arises from animal studies showing that gonadal sex hormones dramatically affect reward systems and reward-related behavior. Specifically, E elevates ventral striatal dopamine and accelerates both drug-cued and drug-primed reinstatement, while P has opposite effects on drug-seeking behavior. Correspondingly, when women have high E levels, such as those occurring during the late follicular phase of the MC, they may find drugs more rewarding and drug-related cues more motivating, which could markedly undermine women's success in quitting smoking at that time. Our preliminary neuroimaging results show enhanced responses to SCs in the medial orbitofrontal cortex, a region known to be involved in the coding of reward magnitude, in women during the follicular compared to the luteal phase, but the direct effects of the hormonal milieu on neural responses to SCs remains untested, divesting us of critical, treatment-relevant information. Thus, the overarching goal of this proposal is to characterize the influence of the natural hormonal milieu on brain and behavioral responses to SCs. Specifically, in AIM 1, to link hormonal status to the brain responses to SCs, over the course of 3 monthly MCs, in a repeated measures counter- balanced design, we will compare the brain responses to highly appetitive SCs in a group of healthy, naturally- cycling females who are chronic smokers at 3 distinct time points within their natural MC. Given that the early follicular phase is associated with extremely low levels of both E and P, it offers a natural and ideal comparator condition. Sessions will be carefully timed to occur during high E, which corresponds to the late follicular phase, during high P, which corresponds to the mid-luteal phase, and during the time of the MC when both E and P are low (LEP). E/P concentrations will be used to verify conditions and as covariates to examine their associations with brain responses. In AIM 2, to link hormonal status and brain responses to the behavioral biases to SCs, in synchrony with the imaging sessions, women from Aim 1 will also participate in 3 laboratory sessions consisting of a neuro-behavioral battery that includes tasks to probe affective and attentional biases to SCs at both time points. This research addresses a critical gap in our knowledge: namely, the impact of the hormonal milieu on brain response to SCs, an important relapse trigger. The results may guide hormonally- informed treatment strategies with the potential to reduce relapse, thus improving health and saving lives.

然而，吸烟是美国可预防死亡的头号原因，尽管已知 吸烟的健康后果，五分之一的美国人继续吸烟。大多数吸烟者都想戒烟，但 成功率很低。女性戒烟难度更大，与吸烟相关的痛苦也更大 对健康的影响比男性更大。对女性复发易感性的更多了解可能有助于识别 治疗目标和结果是改善健康和拯救生命的干预措施。这方面的指导性假设 有观点认为，性激素[雌二醇(E)和孕酮(P)]在 月经周期(MC)可能通过对强大的复发的行为而极大地影响复发的易感性 激励因素，吸烟相关线索(SC)暴露。这一假说源于动物研究表明，性腺 性激素极大地影响奖励系统和与奖励相关的行为。具体地说，E提升腹侧 纹状体多巴胺和促进药物提示和药物诱导的恢复，而P则相反 关于寻找毒品的行为。相应地，当女性的E水平较高时，例如在 在MC的卵泡期晚期，他们可能会发现药物更有回报，与药物有关的线索更具激励作用， 这可能会显著削弱当时女性戒烟的成功。我们的预赛 神经成像结果显示，在内侧眶前叶皮质，该区域对干细胞的反应增强 与黄体期相比，女性在卵泡期参与了奖励大小的编码，但 激素环境对神经对干细胞反应的直接影响仍未得到测试，使我们失去了关键的， 与治疗相关的信息。因此，这项提案的首要目标是描述 自然荷尔蒙环境对大脑和对干细胞的行为反应。具体来说，在AIM 1中，将荷尔蒙 在3个月的MC过程中，重复测量反措施的大脑对SCs的反应的状况 平衡设计，我们将比较一组健康的，自然的， 骑自行车的女性，在她们的自然MC内的三个不同的时间点是长期吸烟者。考虑到早期的 卵泡期与极低的E和P水平有关，它提供了一个自然和理想的比较指标 条件。会议将被仔细地安排在高E期间进行，这对应于卵泡晚期， 在对应于黄体中期的高P期间，以及在E和P都处于MC期间 都很低(LEP)。E/P浓度将用于验证条件，并作为协变量检查其 与大脑反应的联系。在AIM 2中，将激素状态和大脑反应与行为 偏向干细胞，与成像课程同步，来自AIM 1的女性也将参加3个实验室 课程由神经行为电池组成，其中包括探测情感和注意力偏差的任务 在这两个时间点发送给SCS。这项研究解决了我们知识中的一个关键缺口：即 荷尔蒙环境对干细胞对大脑的反应，这是一个重要的复发触发因素。这一结果可能会指导荷尔蒙- 知情的治疗策略，有可能减少复发，从而改善健康和挽救生命。

项目成果

Impact of the natural hormonal milieu on ventral striatal responses to appetitive cigarette smoking cues: A prospective longitudinal study.

• DOI: 10.1016/j.dadr.2022.100119
• 发表时间: 2022-12
• 期刊: Drug and alcohol dependence reports
• 作者: Franklin, Teresa R;Spilka, Nathaniel H;Keyser, Heather;Maron, Melanie;Jagannathan, Kanchana;Wetherill, Reagan R
• 通讯作者: Wetherill, Reagan R