Involvement of Aldehydes in Alcohol Addiction

醛与酒精成瘾有关

• 批准号: 7547079
• 负责人: WILLIAM J MCBRIDE
• 金额: $ 25.14万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547079
• 关键词: Acetaldehyde; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Aldehydes; Animal Model; Arts; Biological Assay; Calcium; Cephalic; Chronic; Data; Dependency; Development; Dopamine; Dose; Ethanol; Heterogeneity; Infusion procedures; Lead; Left; Link; Maintenance; Microdialysis; Microinjections; Nucleus Accumbens; Oral; Rattus; Recording of previous events; Research Design; Rewards; Schedule; Self Administration; Site; Support System; Techniques; Testing; Tetrahydroisoquinolines; Time; Tissues; Triazoles; Ventral Tegmental Area; Wistar Rats; adduct; alcoholism therapy; catalase; chronic alcohol ingestion; design; dopaminergic neuron; drinking behavior; extracellular; in vivo; inhibitor/antagonist; meetings; mesolimbic system; novel; regional difference; response; salsolinol

The long-range objectives of this proposal are to better understand the involvement of acetaldehyde (ACD) and tetrahydroisoquinolines (THIQs) in the development of alcoholism. The overall hypothesis to be tested in the present proposal is that the CNS formation of ACD from ethanol (EtOH), and salsolinol (SAL) from ACD and dopamine (DA) contribute to the promotion of high alcohol drinking behavior. The alcohol-preferring (P) line of rats meets the criteria as an animal model of alcoholism, and is a well accepted animal model for studying mechanisms underlying high alcohol drinking behavior. State-of-the-art intracranial selfadministration (ICSA), in vivo microdialysis and site-selective microinjection techniques, and a highly sensitive SAL assay will be used to test the overall hypothesis. Aim 1 will be designed to determine the effects of chronic 24-hr free-choice EtOH drinking by P rats on CNS tissue levels of SAL and on the extracellular levels of SAL in the nucleus accumbens (NAC) shell. Aim 2 will determine the effects of local microinjections of a catalase inhibitor (3-amino-1, 2,4-triazole [tnazole]), ACD or SAL into the posterior ventral tegmental area (VTA) or NAC-shell on the acquisition and maintenance of operant oral self-administration of EtOH. Aim 3 will determine the dose-response effects for the ICSA of SAL into the VTA and ACD into the NAC-shell of P rats and establish if sub-regional differences exist for the reinforcing effects of these two compounds. In addition, this aim will determine the dose-response effects for the ICSA of ACD and SAL into the VTA and NAC of Wistar rats and whether these effects are different from the dose-response effects obtained with P rats. Aim 4 will use the ICSA technique to determine the interactions of ACD and SAL within the posterior VTA and NAC-shell of P rats on the reinforcing actions of EtOH, and whether a history of alcohol drinking impacts on these interactions. Aim 5 will determine the extracellular levels of SAL and DA in the NAC-shell and VTA during EtOH self-administration under scheduled access conditions. These findings will provide an important link between alcohol drinking and the formation of ACD and SAL within the mesolimbic DA system, and the impact that these compounds may have in enhancing the rewarding actions of EtOH and promoting high alcohol drinking. Understanding the contribution of ACD and THIQs to high alcohol drinking could lead to the development of novel pharmaco-therapies for the treatment of alcoholism and alcohol abuse

该提案的长期目标是更好地了解乙醛（ACD）和四氢异喹啉（THIQ）在酒精中毒发展中的作用。本提案中要测试的总体假设是，中枢神经系统从乙醇 (EtOH) 形成 ACD，以及从 ACD 和多巴胺 (DA) 形成仙人掌醇 (SAL)，有助于促进高度饮酒行为。大鼠的酒精偏好（P）系符合酒精中毒动物模型的标准，并且是研究高酒精饮酒行为背后机制的公认的动物模型。最先进的颅内自我给药（ICSA）、体内微透析和位点选择性显微注射技术以及高灵敏度的 SAL 测定将用于检验总体假设。目标 1 旨在确定 P 大鼠长期 24 小时自由选择 EtOH 饮用对中枢神经系统组织 SAL 水平以及伏隔核 (NAC) 壳中 SAL 细胞外水平的影响。目标 2 将确定过氧化氢酶抑制剂（3-氨基-1, 2,4-三唑 [tnmaze]）、ACD 或 SAL 局部显微注射到后腹侧被盖区 (VTA) 或 NAC-shell 对采集和维持操作性口服自我给药乙醇。目标 3 将确定 SAL 进入 VTA 的 ICSA 和 ACD 进入 P 大鼠 NAC-壳的剂量反应效应，并确定这两种化合物的增强作用是否存在次区域差异。此外，该目标将确定ACD和SAL的ICSA对Wistar大鼠的VTA和NAC的剂量反应效应，以及这些效应是否与P大鼠获得的剂量反应效应不同。目标 4 将使用 ICSA 技术来确定 P 大鼠后 VTA 和 NAC-shell 内 ACD 和 SAL 对 EtOH 增强作用的相互作用，以及饮酒史是否对这些相互作用产生影响。目标 5 将确定在预定访问条件下 EtOH 自我管理期间 NAC-shell 和 VTA 中 SAL 和 DA 的细胞外水平。这些发现将提供饮酒与中脑边缘 DA 系统内 ACD 和 SAL 形成之间的重要联系，以及这些化合物在增强 EtOH 的奖励作用和促进大量饮酒方面可能产生的影响。了解 ACD 和 THIQ 对大量饮酒的影响可能有助于开发治疗酒精中毒和酒精滥用的新型药物疗法