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

描述：(摘自申请者的摘要)尼古丁成瘾是基础 烟草产品的广泛使用。流行病学证据表明 青少年时期就开始吸烟的人患上 终身吸烟者比在20岁或更晚的S开始吸烟的人更多。 关于大脑发育和衰老的可能影响的数据很少。 尼古丁对其分子和代谢的影响 行为和令人上瘾的特性。这项研究将调查 尼古丁贴片或安慰剂对人体志愿者的急性给药 (不吸烟者和依赖吸烟者；年龄范围为14-20岁和35-45岁) 高能磷酸盐[磷酸肌酸和5‘-三磷酸腺苷] 和膜磷脂代谢[磷单酯(PME)和 磷酸二酯(PDE)]31P磁共振波谱成像(MRSI) 以及N-乙酰天冬氨酸的量度(一种假定的神经元量度 完整性)、三甲胺[甘油磷胆碱、磷胆碱和 胆碱]和肌酸(Cr)(聚合酶链式反应+肌酸)。短相关时间( S)和中间关联时间(I-TC)分量的关系 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) 膜磷脂的分解产物和PDE(I-TC)反映了 灰质内突触小泡的数量。受试者年龄和年龄的影响 吸烟状态对尼古丁的分子和代谢反应将是 调查过了。此外，定量1H磁共振成像(MRI) 将执行以将代谢结果与百分比相关联 感兴趣体素中的灰质、白质和脑脊液 获得了MRSI数据。我们的31P-1HMRSI试验数据在两个非吸烟者中 年龄组(青年-成人和中年受试者)提示尼古丁诱导 膜磷脂的瞬时分解为PDE(S-TC)，然后 PME(S-TC)。尼古丁诱导的PDE(I-TC)也似乎减少。 可能与突触一过性减少有关的灰质水平 水泡。试点数据表明尼古丁的反应更为强劲。 在青壮年不吸烟者中比中年不吸烟者和 尼古丁对青年和成人不同脑区的反应 中年非吸烟者。我们建议研究大脑的这些方面 用31P-1HMRSI研究人体代谢。

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.