GABAergic Mechanisms of Comorbid Alcohol and Nicotine Dependence

共病酒精和尼古丁依赖的 GABA 机制

• 批准号: 7783876
• 负责人: Kelly P Cosgrove
• 金额: $ 44.89万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7783876
• 关键词: Abstinence; Acute; Address; Adolescent; Age; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Anesthesia procedures; Animals; Area; Behavioral; Benzodiazepine Receptor; Benzodiazepines; Binding; Brain; Brain Chemistry; Brain imaging; Cerebrospinal Fluid; Chemicals; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Treatment; Comorbidity; Consumption; Control Groups; Controlled Environment; Data; Documentation; Drug Exposure; Drug Interactions; Ethanol; Exhibits; Exposure to; GABA Receptor; Gray unit of radiation dose; Human; Image; Imaging Techniques; Individual; Intake; Life; Link; MRI Scans; Macaca; Macaca mulatta; Magnetic Resonance Imaging; Male Adolescents; Measures; Mediating; Mental disorders; Modeling; Molecular; Nature; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Oral; Pharmaceutical Preparations; Population; Public Health; Recovery; Regulation; Relapse; Reporting; Research; Saccharin; Scanning; Self Administration; Self-Administered; Severities; Site; Smoke; Smoker; Smoking; Subgroup; System; Testing; Time; Tobacco smoke; Tobacco smoking; Withdrawal; Withdrawal Symptom; addiction; alcohol effect; alcohol use initiation; base; behavior change; chronic alcohol ingestion; cigarette smoking; cigarette smoking; comparison group; drinking; follow-up; human data; human subject; in vivo; iomazenil; neurochemistry; non-smoker; nonhuman primate; problem drinker; programs; public health relevance; receptor; receptor density; recidivism; research study; single photon emission computed tomography; smoking cessation; time use; treatment strategy; uptake; white matter

DESCRIPTION (provided by applicant): Alcohol dependence and tobacco smoking are highly associated, yet studies examining the underlying neurochemistry are scarce. In humans, tobacco smoking appears to regulate the availability of the GABAA- BZR during the recovery from alcohol dependence. Clinical data suggest increased GABAA-BZR availability in alcohol dependent nonsmokers during acute withdrawal that is suppressed in alcohol dependent smokers. Additionally, there appears to be decreased GABAA-BZR availability during prolonged alcohol withdrawal; yet this has not been systematically studied. The purpose of this project is to determine the effects of withdrawal from chronic orally-delivered ethanol versus chronic co-administration of ethanol and nicotine on the GABAA- BZR in brain over time using [123I]iomazenil and single photon emission computed tomography (SPECT). We will also examine changes in GABAA-BZR availability during withdrawal from both ethanol and nicotine simultaneously, versus withdrawal from ethanol in the presence of continued nicotine exposure to model changes in GABAA-BZR in humans that quit drinking and smoking simultaneously vs. quitting drinking while continuing to smoke. We will obtain scans in 50 adolescent animals (n=10 per group). All animals will receive 2 scans at baseline, e.g., test-retest. Group 1 will self-administer chronic ethanol for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 2 will self-administer chronic nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 3A will self-administer ethanol plus nicotine for 24 weeks and will be scanned at 1 day, 8 days and 12 weeks withdrawal from both ethanol and nicotine. Group 3B will self-administer ethanol plus nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal from ethanol, but will continue to self-administer nicotine during this withdrawal period. Group 4, a control condition, will self-administer saccharin for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks after termination of saccharin. MRI scans will be obtained to track changes in brain gray and white matter and cerebrospinal fluid (CSF). We hypothesize that there will be 1) increased GABAA-BZR availability compared to baseline and controls during acute ethanol withdrawal and decreased GABAA-BZR availability compared to baseline and controls at 12 weeks ethanol withdrawal; 2) no change in GABAA-BZR availability compared to baseline or controls during nicotine withdrawal; and, 3) the combination of ethanol and nicotine will result in decreased GABAA-BZR availability compared to ethanol alone, i.e., nicotine will suppress the ethanol-induced increase, and withdrawal from ethanol into the presence of nicotine will result in a greater suppression of increased GABAA-BZR availability compared to withdrawal from ethanol and nicotine simultaneously. The findings from this study will advance the understanding of the neurochemical mechanisms that underlie the high comorbidity of alcohol and nicotine dependence and will have direct clinical implications for the treatment of alcohol dependence in both smokers and nonsmokers. PUBLIC HEALTH RELEVANCE: The proposed experiments will directly impact public health by delineating a brain mechanism, the GABAA- benzodiazepine receptor, which is involved in the recovery from alcohol dependence and in the interaction of alcohol dependence and tobacco smoking. These studies will examine the withdrawal from both alcohol and nicotine to determine the interaction of these drugs on brain chemistry. These studies will ultimately provide information on how to more successfully treat these costly addictions.

描述（由申请人提供）：酒精依赖和烟草吸烟是高度关联的，但是研究了基本神经化学的研究很少。在人类中，烟草吸烟似乎调节了在酒精依赖中恢复期间Gabaa-bzr的可用性。临床数据表明，在急性戒断期间，依赖酒精的吸烟者抑制酒精的非吸烟者的GABAA-BZR可用性增加。此外，在长时间戒酒期间，GABAA-BZR的可用性似乎降低了。然而，这尚未系统地研究。该项目的目的是使用[123i] iomazenil和单个光子发射计算机摄影（SPECT），确定乙醇和尼古丁从慢性口服乙醇与慢性共同给药的影响。我们还将在同时从乙醇和尼古丁中退出期间的GABAA-BZR可用性变化，而在尼古丁在持续的尼古丁持续暴露的情况下，与乙醇的戒断相对于人类GABAA-BZR的模型变化，他们在不再饮酒和吸烟的同时戒烟同时戒烟同时戒烟同时吸烟而在继续吸烟的同时戒烟。我们将在50只青少年动物中进行扫描（每组n = 10个）。所有动物将在基线时进行2次扫描，例如重新测试。第1组将自我管理慢性乙醇24周，并将在1天和12周撤离时成像。第2组将自我管理慢性尼古丁24周，并将在1天和12周撤离时成像。第3A组将自助乙醇加上尼古丁24周，并将在1天，8天和12周从乙醇和尼古丁提取。第3B组将自助乙醇加上尼古丁24周，并将在1天，8天和12周从乙醇中提取，但在此退出期间将继续自动辅助尼古丁。第4组是一种对照条件，将自我辅助糖精24周，并在终止糖精后的1天，8天和12周时成像。将获得MRI扫描以跟踪脑灰质和白质以及脑脊液（CSF）的变化。我们假设与基线和急性乙醇戒断期间的基线和对照相比，GABAA-BZR的可用性将增加1）与基线相比，与基线相比，GABAA-BZR的可用性降低了，而在12周乙醇退出时的对照组则相比。 2）与尼古丁戒断期间的基线或对照相比，GABAA-BZR的可用性没有变化； 3）与单独乙醇相比，乙醇和尼古丁的结合将导致GABAA-BZR的可用性降低，即尼古丁将抑制乙醇引起的增加，并从乙醇中退出尼古丁的存在将导致与Gabaa-BZR可用性更大的抑制与GABAA-BZR的可用性相比，与乙醇的脱甲醇相比，相比之下。这项研究的发现将提高人们对酒精和尼古丁依赖性高度合并症的神经化学机制的理解，并将对吸烟者和非吸烟者的酒精依赖性的治疗具有直接的临床意义。公共卫生相关性：拟议的实验将通过描述大脑机制Gabaa-Benzodiazepine受体直接影响公共卫生，该受体与酒精依赖以及酒精依赖和吸烟的相互作用有关。这些研究将检查从酒精和尼古丁的提取，以确定这些药物在脑化学上的相互作用。这些研究最终将提供有关如何更成功地处理这些昂贵成瘾的信息。