IN VIVO 31P-1H MRSI AND MRI BRAIN STUDIES OF NICOTINE

尼古丁的体内 31P-1H MRSI 和 MRI 脑部研究

• 批准号: 6607987
• 负责人: JAY W PETTEGREW
• 金额: $ 46.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-29 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607987
• 关键词: adenosine triphosphate; adolescence (12-20); aminoacid analog; aspartate; bioimaging /biomedical imaging; brain metabolism; choline; clinical research; creatine; creatine phosphate; drug addiction; glycerophosphorylcholine; human middle age (35-64); human subject; magnetic resonance imaging; membrane lipids; neuropharmacology; nicotine; nuclear magnetic resonance spectroscopy; phosphoric ester; phosphorylcholine; transdermal drug delivery; young adult human (21-34)

DESCRIPTION: (Adapted from applicant's abstract) Nicotine addiction underlies the widespread use oftobacco products. Epidemiological evidence suggests that individuals who begin smoking as adolescents have a higher probability of being life-long smokers than individuals who start smoking in their 20's or later. There is little data on the possible influence ofbrain developmentand aging onthe molecular and metabolic effects ofnicotine whichcould contnbutc to its behavioral and addictive properties. This studywill investigate the effect of acute administration of eithernicotine by patch or placebo to human volunteers (nonsmokers and dependent smokers;age ranges 14-20and 35-45 years) on measures of high-energy phosphate [phosphocreatine (PCr) and adenosine 5'-triphosphate] and membrane phospholipid metabolism [phosphomonoesters (PME) and phosphodiesters (PDE)] by 31P magnetic resonance spectroscopic imaging (MRSI) and on measures of N-acetylaspartate ( a putative measure of neuronal integrity), trimethylamines [glycerophosphocholine, phosphocholine, and choline], and creatine (Cr) (PCr+Cr) by 1HMRSI. Both short correlation time ( S-Tc) and intermediate correlation time (I-Tc) components of the PME and PDE resonances will be quantified. The PME (S-Tc) are precursors of membrane phospholipids and the PME (i-tc) are phosphorylated proteins. The PDE (S-Tc) are breakdown products of membrane phospholipids and PDE (I-Tc) reflect the number of synaptic vesicles in grey matter. The influence of subject age and smoking status on the molecular and metabolic responses to nicotine will be investigated. In addition, quantitative 1H magnetic resonance imaging (MRI) will be performed in order to correlate the metabolic findings with the percent gray matter, white matter, and CSF in the voxels of interest from which the MRSI data is obtained. Our 31 P-1H MRSI pilot data in human nonsmokers in two age groups (young-adult and middle-aged subjects) suggests nicotine-induced transient breakdown of membrane phospholipids to PDE (s-Tc) and then to PME(S-Tc). There also appears to be a nicotine-induced decrease in PDE(i-Tc) levels in grey matter which could be related to transient reduction in synaptic vesicles. The pilot data indicates more robust changes in response to nicotine in the young-adult nonsmokers than in the middle-aged nonsmokers and a nicotine-induced response in different brain regions for young-adult versus middle-aged nonsmokers. We propose to investigate these aspects of brain metabolism in humans using 31P-1H MRSI.

描述：（改编自申请人的摘要）尼古丁成瘾的基础 烟草制品的广泛使用。流行病学证据表明 在青少年时期开始吸烟的人更有可能成为 终生吸烟者比 20 多岁或以后开始吸烟的人要多。 关于大脑发育和衰老可能产生的影响的数据很少 尼古丁的分子和代谢作用可能有助于其 行为和成瘾特性。这项研究将调查的影响 通过贴片或安慰剂对人类志愿者进行急性尼古丁给药 （非吸烟者和依赖吸烟者；年龄范围 14-20 岁和 35-45 岁）措施 高能磷酸盐[磷酸肌酸 (PCr) 和 5'-三磷酸腺苷] 和膜磷脂代谢[磷酸单酯（PME）和 磷酸二酯 (PDE)] 通过 31P 磁共振波谱成像 (MRSI) 以及 N-乙酰天冬氨酸的测量（神经元的假定测量） 完整性）、三甲胺[甘油磷酸胆碱、磷酸胆碱和 胆碱]和肌酸 (Cr) (PCr+Cr)（1HMRSI）。相关时间都很短（ PME 和 PDE 的 S-Tc) 和中间相关时间 (I-Tc) 分量 共振将被量化。 PME (S-Tc) 是膜的前体 磷脂和 PME (i-tc) 是磷酸化蛋白质。偏微分方程 (S-Tc) 是膜磷脂的分解产物，PDE (I-Tc) 反映了 灰质中突触小泡的数量。受试者年龄的影响 吸烟状况对尼古丁分子和代谢反应的影响 调查了。此外，定量 1H 磁共振成像 (MRI) 将进行以便将代谢结果与百分比相关联 感兴趣的体素中的灰质、白质和脑脊液 获得 MRSI 数据。我们在人类非吸烟者中的 31 个 P-1H MRSI 试验数据分为两部分： 年龄组（青年和中年受试者）表明尼古丁诱发 膜磷脂瞬时分解为 PDE (s-Tc)，然后分解为 PME（S-Tc）。尼古丁似乎还会导致 PDE(i-Tc) 降低 灰质中的水平可能与突触的短暂减少有关 囊泡。试点数据表明对尼古丁的反应发生了更强劲的变化 年轻的不吸烟者的比例高于中年不吸烟者，而且 尼古丁在年轻人和成年人不同大脑区域引起的反应 不吸烟的中年人。我们建议研究大脑的这些方面 使用 31P-1H MRSI 进行人体新陈代谢。