Involvement of Aldehydes in Alcohol Addiction

这项建议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。本研究拟验证的总体假设是，乙醇产生的ACD(乙醇)和ACD产生的丹参素(SAL)和多巴胺(DA)形成的中枢神经系统有助于促进高酒精饮酒行为。大鼠的酒精偏好(P)系符合酒精中毒动物模型的标准，是研究高酒精饮酒行为机制的公认的动物模型。将使用最先进的颅内自我给药(ICSA)、体内微透析和局部选择性微注射技术以及高灵敏度的SAL分析来检验整个假设。目的1研究慢性24小时自由饮用乙醇对大鼠中枢神经系统组织和伏核(NAC)壳细胞外SAL水平的影响。目的2确定局部微量注射过氧化氢酶抑制剂(3-氨基-1，2，4-三氮唑[替硝唑])、ACD或SAL到腹后被盖区(VTA)或NAC-壳体内对EtoH获得和维持的影响。目的3测定SAL对P大鼠VTA和ACD增强作用的量效关系，并确定这两种化合物的增强作用是否存在区域差异。此外，本研究还将确定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大鼠的剂量-反应效应不同。目的用ICSA技术研究P鼠VTA后部和NAc-壳内ACD和SAL对乙醇强化作用的相互作用，以及饮酒史是否影响这种相互作用。AIM 5将测定在预定进入条件下，乙醇自我给药过程中NAC-壳和VTA中SAL和DA的胞外水平。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乙醇的奖赏作用和促进高酒精饮酒方面可能产生的影响。了解ACD和THIQ在高酒精饮酒中的作用可能会导致开发治疗酒精中毒和酒精滥用的新药物疗法

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