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.

项目摘要/摘要 吸烟是美国妇女可预防死亡和疾病的主要原因 受吸烟的影响，因为它们不仅有较高的风险会遭受吸烟的健康后果的影响 例如心脏病，但也遭受特定性别的健康问题，包括宫颈癌。女人还有更多 难以维持吸烟的长期禁欲，可能是因为他们经历更强大 恢复吸烟后的戒断症状和这些症状的缓解。尽管它们增强了 对吸烟疗法的需求，当前的一线治疗（例如尼古丁替代品）较少 对女性有效。驱动这些性别差异的大脑功能的潜在差异 保持未知，理解它们可以指导个性化戒烟疗法的开发。 谷氨酸能神经传递是戒烟疗法的有前途的新目标，但性 整个大脑谷氨酸水平的差异，可能会影响谷氨酸能治疗的功效 没有在吸烟者中调查。我们使用单素磁共振光谱的初步数据 （MRS），揭示了背扣带回谷氨酸关系的重要性别差异 皮质（DACC），一个高度与烟草使用障碍有关的地区，性别（男性与女性）和吸烟 烟民中的状态（隔夜避免与烟熏后）。而且，DACC中的谷氨酸也是相关的 在吸烟的女性中循环雌激素，可能是孕酮。但是，重要的关系 在其他大脑区域的谷氨酸和这些因素之间尚待探索。回声平面光谱 成像（EPSI）是一种最先进的技术，允许在约80％的整体中测量谷氨酸 人体内的大脑。鉴于我们使用单素MRS的初步结果，我们现在建议测试 我们在DACC中发现的可复制性，并严重检查向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 - 前岛和丘脑。我们也会 对性，吸烟状态和卵巢进行谷氨酸关系的探索性分析 激素。 否则健康的成人日常吸烟者（30名男性和30名女性）将作为这项研究的参与者。他们 过夜（〜12 h）戒烟和吸烟后，将对两次进行测试 天。我们将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。 确定吸烟对脑谷氨酸的急性影响的性别差异。这项研究的发现将 提供有关吸烟者中大脑谷氨酸水平的重要经验信息，并指导 开发个性化的，性别特定的戒烟疗法。