Involvement of Aldehydes in Alcohol Addiction

点击翻译按钮获取中文摘要

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