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

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， 青少年时期开始吸烟的人， 终身吸烟者比20多岁或更晚开始吸烟的人更容易吸烟。 关于大脑发育和衰老的可能影响的数据很少 尼古丁的分子和代谢效应，这可能会影响其 行为和成瘾特性。本研究将探讨 通过贴剂或安慰剂对人类志愿者急性施用尼古丁 （非吸烟者和依赖性吸烟者;年龄范围14- 20岁和35-45岁） 高能磷酸盐[磷酸肌酸（PCr）和腺苷5 '-三磷酸] 和膜磷脂代谢[磷酸单酯（PME）和 磷酸二酯（PDE）]通过31 P磁共振光谱成像（MRSI） 和N-乙酰天冬氨酸的措施（一个假定的措施，神经元 完整性），三甲基胺[甘油磷酸胆碱，磷酸胆碱，和 胆碱]和肌酸（Cr）（PCr+Cr）。两个短相关时间（ S-Tc）和中间相关时间（I-Tc）分量 共振将被量化。PME（S-Tc）是成膜前体 磷脂和PME（i-tc）是磷酸化蛋白质。PDE（S-Tc） 是膜磷脂的分解产物，PDE（I-Tc）反映了 灰质中突触囊泡的数量。受试者年龄和 吸烟状况对尼古丁分子和代谢反应的影响 研究了此外，定量1H磁共振成像（MRI） 为了将代谢结果与百分比相关联， 灰质、白色物质和感兴趣体素中的CSF， 获得MRSI数据。我们的31 P-1H MRSI试验数据在人类非吸烟者在两个 年龄组（成人和中年受试者）表明尼古丁诱导的 膜磷脂瞬时分解为PDE（s-Tc），然后 PME（S-Tc）。尼古丁诱导的PDE（i-Tc）降低 灰质中的水平，这可能与突触的短暂减少有关， 囊泡试验数据表明，尼古丁对人体的影响更大， 在中年不吸烟者中， 尼古丁诱导的反应，在不同的大脑区域， 不吸烟的中年人我们打算研究大脑的这些方面 使用31 P-1H MRSI在人体中进行代谢。

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.