Mapping brain glutamate in humans: sex differences in cigarette smokers

绘制人类大脑谷氨酸图谱：吸烟者的性别差异

• 批准号: 10376214
• 负责人: Jeffry R Alger
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376214
• 关键词: 3-Dimensional; Abstinence; Acetylcysteine; Acute; Address; Adult; Advanced Development; Affect; Anatomy; Anterior; Antismoking; Attenuated; Behavioral; Biological Assay; Biological Markers; Brain; Brain Mapping; Brain region; Cigarette; Cigarette Smoker; Cues; Cysteine; Cytology; Data; Development; Disease; Dopamine; Dorsal; Estrogens; Excitatory Amino Acid Antagonists; Female; Functional Magnetic Resonance Imaging; Glutamate Transporter; Glutamates; Glutamine; Health; Heart Diseases; Human; Imaging Techniques; Insula of Reil; Libido; Link; Magnetic Resonance Spectroscopy; Maintenance; Malignant neoplasm of cervix uteri; Measurement; Measures; N-Methylaspartate; Nicotine; Nicotine Withdrawal; Nicotinic Receptors; Ovarian hormone; Participant; Progesterone; Radiation exposure; Resolution; Rest; Rodent; Sampling; Satiation; Self Administration; Serum; Sex Differences; Signal Transduction; Smoke; Smoker; Smoking; Sum; Techniques; Testing; Thalamic structure; Time; Tissues; Tobacco Use Disorder; Treatment Efficacy; Variant; Withdrawal Symptom; Woman; addiction; antiporter; cigarette craving; cigarette smoking; cingulate cortex; density; experience; extracellular; glutamatergic signaling; high risk; improved; in vivo; male; men; neuropsychiatric disorder; neurotransmission; nicotine replacement; nicotine seeking behavior; non-smoker; novel; personalized medicine; preventable death; reduce symptoms; segregation; sex; smoking abstinence; smoking cessation; smoking intervention; specific biomarkers; spectroscopic imaging; treatment response; varenicline

PROJECT SUMMARY/ABSTRACT Smoking is the leading cause of preventable death and disease in the U.S. Women are disproportionately affected by smoking, as they not only have a higher risk of experiencing some health consequences of smoking, such as heart disease, but also suffer sex-specific health issues, including cervical cancer. Women have more difficulty maintaining long-term abstinence from smoking than men, possibly because they experience stronger withdrawal symptoms and greater relief of these symptoms after resumption of smoking. Despite their enhanced need for smoking-cessation therapies, current first-line treatments, such as nicotine replacement, are less effective for women than men. The underlying differences in brain function that drive these sex differences remain unknown, and understanding them can guide development of personalized smoking cessation therapies. Glutamatergic neurotransmission is a promising new target for smoking cessation therapy, but sex differences in glutamate levels across the brain, which can impact the efficacy of glutamatergic treatments, have not been investigated in smokers. Our preliminary data using single-voxel magnetic resonance spectroscopy (MRS), have revealed important sex differences in the relationships of glutamate in the dorsal anterior cingulate cortex (dACC), a region highly implicated in Tobacco Use Disorder, with sex (males vs. females) and smoking state (overnight abstinent vs. post-smoking) in smokers. Moreover, glutamate in the dACC is also associated with circulating estrogen, and possibly progesterone, in women who smoke. However, important relationships between glutamate in other brain regions and these factors are yet to be explored. Echo-planar spectroscopic imaging (EPSI), a state-of-the-art technique, permits measurement of glutamate in ~80 percent of the whole brain in vivo in humans. Given our preliminary results using single-voxel MRS, we now propose to test replicability of our finding in the dACC and to examine potential extension to other brain regions heavily implicated in the behavioral states of Tobacco Use Disorder - the anterior insula and thalamus. We will also perform exploratory analyses of relationships of glutamate across the brain with sex, smoking state, and ovarian hormones. Otherwise healthy, adult daily smokers (30 men and 30 women) will serve as participants for this study. They will be tested twice, after overnight (~12 h) abstinence from smoking and after smoking their first cigarette of the day. We will combine EPSI with analysis of circulating ovarian hormones in serum to address two specific aims: Aim 1. Determine relationships between brain glutamate, sex, and circulating ovarian hormones. Aim 2. Determine sex differences in acute effects of smoking on brain glutamate. The findings from this study will provide important empirical information regarding glutamate levels across the brain in smokers and help guide development of personalized, sex-specific smoking cessation therapies.

项目总结/摘要 在美国，吸烟是可预防的死亡和疾病的主要原因。 受吸烟影响，因为他们不仅有更高的风险经历吸烟的一些健康后果， 如心脏病，但也遭受性别特有健康问题，包括宫颈癌。女性有更多 比男性更难保持长期戒烟，可能是因为他们经历了更强的 戒断症状和恢复吸烟后这些症状的更大缓解。尽管他们增强了 由于对戒烟疗法的需求较少，目前的一线治疗方法（例如尼古丁替代疗法）较少 对女性比男性更有效。导致这些性别差异的大脑功能的潜在差异 目前尚不清楚，了解它们可以指导个性化戒烟疗法的发展。 谷氨酸能神经传递是戒烟治疗的一个有前途的新靶点，但性 大脑中谷氨酸水平的差异，这可能会影响谷氨酸能治疗的疗效， 未在吸烟者中进行研究。我们使用单体素磁共振光谱的初步数据 (MRS)，揭示了背侧前扣带回谷氨酸关系的重要性别差异 皮质（dACC），一个与烟草使用障碍高度相关的区域，与性别（男性与女性）和吸烟有关 吸烟者的状态（整夜戒烟vs.吸烟后）。此外，dACC中的谷氨酸也与 与吸烟女性体内循环的雌激素，可能还有孕激素有关。然而，重要的关系 其他脑区的谷氨酸和这些因素之间的关系还有待探索。回波平面光谱 EPSI是一种最先进的技术，可以测量整个大脑中约80%的谷氨酸盐。 在人类体内的大脑。鉴于我们使用单体素MRS的初步结果，我们现在建议测试 我们的发现在dACC中的可复制性，并检查对其他大脑区域的潜在扩展 与烟草使用障碍的行为状态有关-前丘脑和丘脑。我们还将 对大脑中谷氨酸与性别、吸烟状态和卵巢的关系进行探索性分析。 荷尔蒙 本研究的受试者为健康的成年每日吸烟者（30名男性和30名女性）。他们 将在戒烟过夜（约12小时）后和吸完第一支烟后进行两次检测。 天我们将联合收割机EPSI与血清中循环卵巢激素的分析相结合，以解决两个具体目标： 目标1.确定脑谷氨酸，性别和循环卵巢激素之间的关系。目标2. 确定吸烟对大脑谷氨酸盐急性影响的性别差异。这项研究的结果将 提供有关吸烟者大脑中谷氨酸水平的重要经验信息，并帮助指导 开发个性化、性别特异性戒烟疗法。