Involvement of Aldehydes in Alcohol Addiction

这项提案的长期目标是更好地了解乙醛（ACD）和四氢异喹啉（THIQs）在酒精中毒发展中的作用。在本提议中待测试的总体假设是，CNS从乙醇（EtOH）形成ACD，以及从ACD和多巴胺（DA）形成猪毛菜醇（SAL）有助于促进高度饮酒行为。大鼠的酒精偏好（P）系符合作为酒精中毒动物模型的标准，并且是用于研究高度饮酒行为的机制的公认动物模型。将使用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SAL测定来检验总体假设。目的1将被设计为确定慢性24小时自由选择乙醇饮用的P大鼠对中枢神经系统组织水平的SAL和细胞外水平的SAL在延髓核（NAC）壳的影响。目的2将确定局部微量注射过氧化氢酶抑制剂（3-氨基-1，2，4-三唑[tnazole]）、ACD或SAL至后腹侧被盖区（VTA）或NAC壳对获得和维持操作性口服自我给药EtOH的影响。目的3将确定SAL进入P大鼠VTA和ACD进入NAC壳的ICSA的剂量反应效应，并确定这两种化合物的增强效应是否存在亚区域差异。此外，该目的将确定ACD和SAL对Wistar大鼠VTA和NAC的ICSA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。目的4将使用ICSA技术来确定P大鼠后VTA和NAC壳内ACD和SAL对EtOH增强作用的相互作用，以及饮酒史是否影响这些相互作用。目标5将确定在预定入路条件下EtOH自我给药期间NAC壳体和VTA中SAL和DA的细胞外水平。这些研究结果将提供一个重要的联系饮酒和形成ACD和SAL的mesolimbic DA系统内，这些化合物可能会产生的影响，在提高奖励行动的乙醇，促进高酒精饮用。了解ACD和THIQs对高度饮酒的贡献可能会导致开发新的药物治疗酒精中毒和酒精滥用

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