CORTICAL GABA FUNCTION IN ALCOHOLISM

酗酒中的皮质 GABA 功能

• 批准号: 8127631
• 负责人: John H. Krystal
• 金额: $ 68.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127631
• 关键词: Acute; Address; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Applications Grants; Atrophic; Benzodiazepine Receptor; Binding; Blood; Blood Cells; Brain; Brain imaging; Carbolines; Clinical Data; Comorbidity; Complex; Custom; Data; Dependence; Diagnosis; Doctor of Philosophy; Dose; Drops; Emission-Computed Tomography; Ethanol dependence; Funding; GABA A Receptor Binding; GABA Receptor; GABA-A Receptor; Gene Expression; Genes; Genotype; Human; Image; Individual; Leukocytes; Ligand Binding; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediating; Messenger RNA; Molecular; Monitor; Neurons; Nicotine; Patients; Pattern; Pharmaceutical Preparations; Photons; Plasma; Play; Principal Investigator; Public Health; Questionnaires; Recovery; Relapse; Research; Research Personnel; Risk; Role; Safety; Scanning; Sensory Receptors; Severities; Smoke; Smoker; Smoking; Smoking Status; Steroids; System; Techniques; Testing; Time; Tissues; Up-Regulation; Withdrawal; alcohol craving; alcohol effect; base; cDNA Arrays; cigarette smoking; clinically significant; comparison group; cost; drinking; gamma-Aminobutyric Acid; in vivo; interest; iomazenil; monocyte; non-smoker; non-smoking; prevent; programs; receptor; receptor function; response; restoration; sobriety; uptake

DESCRIPTION (provided by applicant): Accomplishments: With the initial support (RO1 AA11321-01A1), we pioneered the concurrent application of magnetic resonance imaging (MRI), magnetic resonance spectroscopy at (MRS), and 1231-iomazenil single photon emission computerized tomography (SPECT) to characterize parallel changes in cortical GABA levels and GABA-A receptors during recovery from alcohol dependence (healthy subjects; patients at 1 week, 1 month, and 6 months of sobriety). Our SPECT data describe increased ligand binding to GABA-A receptors over the first week of sobriety that recovers during the next 3 weeks. These data could reflect a deficit in GABA-A receptor function normalizes with sobriety. Our MRS data indicate that cortical GABA deficts are not present in acute withdrawal, but levels declined over the first month of sobriety as ligand binding to GABA-A receptors dropped. We hypothesize that these shifts reflect a restoration of GABA-A receptor function that is mediated by changes in GABA-A receptor subunit composition. Comorbid smoking blocked the withdrawal-related changes in cortical GABA levels and GABA-A receptors. Thus, GABA systems may mediate a facet of the comorbidity of smoking and drinking. This renewal application would enable us to: 1) demonstrate that rapid time-dependent change in GABA-A receptors with sobriety occur within subjects, 2) replicate the reduction in GABA levels with sobriety using higher field (4.0 T) human MRS, and 3) replicate the protective impact of smoking. Analyses will control for tissue atrophy and GABA- related genotypes. Because GABA-A receptor subunit substitutions may contribute to changes in GABA-A receptor binding, we will relate SPECT binding data to changes in the GABA-related gene expression, including receptor subunits, using gene expression arrays applied to monocytes extracted from subjects at each imaging session.

描述（由申请人提供）： 成就：在最初的支持（RO1 AA11321-01A1）下，我们率先同时应用磁共振成像（MRI）、磁共振波谱（MRS）和 1231-iomazenil 单光子发射计算机断层扫描(SPECT) 表征酒精依赖恢复过程中皮质 GABA 水平和 GABA-A 受体的平行变化（健康受试者；1 周时的患者， 1个月，以及6个月的清醒）。我们的 SPECT 数据描述了在清醒的第一周内配体与 GABA-A 受体的结合增加，并在接下来的 3 周内恢复。这些数据可能反映了清醒状态下 GABA-A 受体功能的缺陷。我们的 MRS 数据表明，急性戒断时不存在皮质 GABA 缺陷，但在清醒的第一个月内，随着配体与 GABA-A 受体的结合下降，皮质 GABA 水平下降。我们假设这些变化反映了 GABA-A 受体功能的恢复，这是由 GABA-A 受体亚基组成的变化介导的。共病吸烟阻断了皮质 GABA 水平和 GABA-A 受体与戒断相关的变化。因此，GABA 系统可能在一定程度上介导吸烟和饮酒合并症。这一更新应用将使我们能够：1) 证明清醒状态下 GABA-A 受体在受试者体内发生快速的时间依赖性变化，2) 使用更高场 (4.0 T) 人类 MRS 复制清醒状态下 GABA 水平的降低，以及 3 ）复制吸烟的保护作用。分析将控制组织萎缩和 GABA 相关基因型。由于 GABA-A 受体亚基取代可能会导致 GABA-A 受体结合的变化，因此我们将使用应用于从受试者中提取的单核细胞的基因表达阵列，将 SPECT 结合数据与 GABA 相关基因表达（包括受体亚基）的变化联系起来。成像会议。