CORTICAL GABA FUNCTION IN ALCOHOLISM

酗酒中的皮质 GABA 功能

• 批准号: 6627905
• 负责人: John H. Krystal
• 金额: $ 43.4万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627905
• 关键词: GABA receptor; alcoholism /alcohol abuse; benzodiazepine receptor; bioimaging /biomedical imaging; brain imaging /visualization /scanning; cerebral cortex; clinical research; drug withdrawal; ethanol; human subject; longitudinal human study; magnetic resonance imaging; neurochemistry; neurotoxicology; neurotransmitter metabolism; nuclear magnetic resonance spectroscopy; single photon emission computed tomography

GABA/A receptors are a major target for ethanol in the brain. Chronic ethanol administration alters many aspects of GABA function in animals. Similarly, post-mortem human studies documented reductions in the density of binding to the benzodiazepine (BZ) site of the GABA/A receptor. Until recently, clinical studies were limited to GABA measurements in blood and cerebrospinal fluid (CSF). These studies suggest that GABA levels are normal in alcohol dependent patients, decline among the first month of sobriety, and recover within 6 months of their last drink. Recent neuroimaging advances now make it possible to measure aspects of GABA function in the human brain in vivo. Our group has advanced the quantification of regional GABA levels in the human cerebral cortex using 1H-magnetic resonance spectroscopy (1H-NMR). Using this technique, our pilot data indicate that GABA levels in the occipital cortex are reduced in male early onset alcoholic patients sober for 1 month relative to a matched group of healthy subjects. We have also contributed to the development of a single photon emission computerized tomography computerized tomography (SPECT) technique, employing [123I]-iomazenil, for assessing a measure, Vt, a measure related to the density of binding to BZ receptors. Employing this technique, we found reductions in frontal and occipital cortex BZ receptor binding from a similar group of recently detoxified alcoholic patients. The principal objective of this proposal is to provide the first longitudinal description of the recovery of brain GABA systems with sobriety in alcohol dependent alcoholic patients. Patients (n=50) would be assessed using both 1H-NMR and SPECT at 3 timepoints in relation to their last drink (,7 days, 1 month, 6 months). The first two assessments (,7 days, 1 month) would be completed as inpatients to insure sobriety. Results from patients would be compared to a matched healthy control group (n=25) studied at similar intervals. Both 1H-NMR and SPECT data would be segmented into components arising from gray matter, white matter, and CSF, providing a correction for gray matter atrophy. Further, metabolites measured simultaneously with GABA during 1H- NMR imaging, such as N-acetylaspartate and creatine, will provide additional information about cortical neuronal viability. Thus, this proposal would provide a multi-dimensional evaluation of GABA disturbances that may help to clarify both the pharmacologic and neurotoxic consequences of alcoholism.

GABA/A 受体是大脑中乙醇的主要靶标。慢性的 乙醇给药改变了动物 GABA 功能的许多方面。 同样，人体尸检研究记录了密度的降低 与 GABA/A 受体的苯二氮卓 (BZ) 位点的结合。直到 最近，临床研究仅限于血液中的 GABA 测量， 脑脊液（CSF）。这些研究表明 GABA 水平 酒精依赖患者的正常情况，在第一个月内下降 清醒，并在上次饮酒后 6 个月内恢复。最近的 神经影像学的进步现在使得测量 GABA 的各个方面成为可能 人脑在体内的功能。我们课题组已先进 定量人类大脑皮层区域 GABA 水平 1H-磁共振波谱(1H-NMR)。使用这种技术，我们的 试验数据表明枕叶皮质中的 GABA 水平降低 男性早发性酗酒患者相对于正常人清醒 1 个月 匹配组的健康受试者。我们也为 单光子发射计算机断层扫描的发展 计算机断层扫描 (SPECT) 技术，采用 [123I]-iomazenil，用于 评估测量值 Vt，与 BZ 结合密度相关的测量值 受体。采用这种技术，我们发现额叶和 枕叶皮层 BZ 受体结合最近来自类似组 戒毒的酒精患者。该提案的主要目标是 提供大脑恢复的第一个纵向描述 酒精依赖型酒精患者的 GABA 系统保持清醒。 患者 (n=50) 将在 3 时使用 1H-NMR 和 SPECT 进行评估 与最后一次饮酒相关的时间点（7 天、1 个月、6 个月）。 前两次评估（7 天，1 个月）将完成为 住院病人要保证清醒。患者的结果将与 匹配的健康对照组（n=25）以相似的时间间隔进行研究。两个都 1H-NMR 和 SPECT 数据将被分割成由灰色产生的成分 质、白质和脑脊液，为灰质提供校正 萎缩。此外，在 1H- 期间与 GABA 同时测量代谢物 NMR 成像，例如 N-乙酰天冬氨酸和肌酸，将提供 有关皮质神经元活力的其他信息。因此，这个 该提案将为 GABA 干扰提供多维评估 这可能有助于澄清药理学和神经毒性 酗酒的后果。