Involvement of Aldehydes in Alcohol Addiction

醛与酒精成瘾有关

• 批准号: 7337989
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337989
• 关键词: Acetaldehyde; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Aldehydes; Animal Model; Arts; Biological Assay; Calcium; Cephalic; Chronic; Condition; Data; Dependency; Development; Dopamine; Dose; Ethanol; Heterogeneity; Infusion procedures; Lead; Left; Link; Maintenance; Microdialysis; Microinjections; Nucleus Accumbens; Oral; Other Finding; Range; 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/alcohol abuse; catalase; chronic alcohol ingestion; design; dopaminergic neuron; drinking behavior; extracellular; in vivo; inhibitor/antagonist; 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

该提案的远程目标是更好地了解乙醛（ACD）和四氢异喹啉（Thiqs）参与酒精中毒的发展。在本提案中要检验的总体假设是，来自乙醇（ETOH）的ACD形成，ACD和多巴胺（DA）的Salsolinol（SAL）（DA）有助于促进高饮酒行为。饮酒（P）的大鼠系列符合酒精中毒模型的标准，并且是研究高酒精饮用行为的机制的良好动物模型。最先进的颅内自我给药（ICSA），体内微透析和现场选择的微注射技术以及高度敏感的SAL分析将用于检验整体假设。 AIM 1的设计旨在确定P大鼠对慢性24小时自由选择ETOH饮用对CNS组织水平的SAL和伏隔核（NAC）壳中SAL的细胞外水平的影响。 AIM 2将确定过氧化氢酶抑制剂（3-AMINO-1，2,4-三唑[TNAZOLE]），ACD或SAL对腹侧腹侧段段区域（VTA）或NAC-shell的局部显微注射对ETOH的获得和维持操作者口服自我施用的影响。 AIM 3将确定SAL的ICSA在VTA中的ICSA和ACD的剂量反应效应到P大鼠的NAC壳中，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，此目的将确定ACD和SAL的ICSA和SAL的剂量反应效应到Wistar大鼠的VTA和NAC中，以及这些作用是否与P大鼠获得的剂量反应效应是否不同。 AIM 4将使用ICSA技术来确定ACD和SAL在p大鼠后VTA和NAC壳中的相互作用在ETOH的强化作用上，以及饮酒的历史是否会对这些相互作用产生影响。 AIM 5将确定在预定的访问条件下ETOH自我管理期间NAC壳和VTA中SAL和DA的细胞外水平。这些发现将提供饮酒与中龙DA系统中ACD和SAL的形成之间的重要联系，以及这些化合物可能对增强ETOH的有意义作用和促进高饮酒的影响。了解ACD和Thiqs对高饮酒的贡献可能会导致新型药物治疗用于治疗酒精中毒和酒精滥用