Involvement of Aldehydes in Alcohol Addiction

本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。本研究的总体假设是乙醇（EtOH）在中枢神经系统中形成的ACD，以及ACD和多巴胺（DA）形成的salsolinol （SAL）有助于促进高酒精饮酒行为。酒精偏好(P)系大鼠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一种广泛接受的动物模型。最先进的颅内自我给药（ICSA），体内微透析和部位选择性微注射技术，以及高度敏感的SAL测定将用于检验整个假设。目的1旨在确定P大鼠慢性24小时自由选择EtOH饮酒对中枢神经系统组织SAL水平和伏隔核（NAC）壳细胞外SAL水平的影响。目的2将确定局部显微注射过氧化氢酶抑制剂（3-氨基- 1,2,4 -三唑[tnazole]）、ACD或SAL到后腹侧被盖区（VTA）或nac -壳对获得和维持手术口服自我给药EtOH的影响。目的3将确定SAL进入VTA和ACD进入P大鼠nac -壳的ICSA的剂量反应效应，并确定这两种化合物的强化作用是否存在次区域差异。此外，本目的目的是确定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4将使用ICSA技术来确定P大鼠后VTA和nac -壳内ACD和SAL对EtOH强化作用的相互作用，以及饮酒史是否对这些相互作用有影响。目的5将确定在预定的准入条件下，EtOH自我给药期间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边缘DA系统中ACD和SAL形成之间的重要联系，以及这些化合物可能在增强EtOH的奖励作用和促进高酒精饮用方面的影响。了解ACD和thiq对高酒精饮酒的影响可能会导致开发治疗酒精中毒和酒精滥用的新型药物疗法

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