Involvement of Aldehydes in Alcohol Addiction

这是一项探索性拨款(R21)，旨在研究乙醛(ACD)和四氢异喹啉(THIQs)在酒精成瘾中的作用。需要检验的总体假设是，ACD和THIQ的形成有助于酒精成瘾。本应用的目的是研究ACD和沙龙醇(SAL)在大鼠中脑边缘多巴胺(DA)系统中的增强作用。本提案将检验以下假设：(A)酸和SAL在酗酒(P)大鼠的腹侧被盖区(VTA)内增强；(B)SAL在P大鼠的伏隔核(NAC)壳内增强；以及(C)ACD和SAL增强P大鼠VTA内的乙醇强化。这些假说将使用颅内自我给药(ICSA)技术来检验ACD和/或SAL在P大鼠的VTA和/或NAC内的强化作用。初步数据表明，雌性P大鼠可自行将6-90 nM的ACD直接注入VTA后部。目前的应用将在雄性P和Wistar大鼠身上扩展这些发现。具体目标1将检查ACD在VTA前部以及VTA附近区域的剂量-反应效应，以确定ACD增强效应的部位。这一目的还将研究ACD在VTA后部的ICSA的消退和恢复。此外，特殊目的1将比较ACD对P和Wistar大鼠VTA后部ICSA的量效关系。具体目标2将检测SAL在P大鼠的VTA和NAc内的剂量反应效应。具体目标3将观察ACD或SAL对乙醇增强P大鼠后VTA的作用。此外，这一目的将检验乙醇向ACD的转化是否可以通过将过氧化氢酶抑制剂与乙醇共同注入P大鼠的后部VTA来支持乙醇的ICSA。这项研究的结果将提供关于ACD和SAL在中边缘系统中的作用的信息，这可能表明这些化合物本身的直接增强作用和/或这些化合物对乙醇增强性质的增强作用。这些结果可以为酒精成瘾的新机制提供有价值的信息，并为未来的神经生物学研究提供坚实的科学基础。

This is an exploratory (R21) grant to examine the involvement of acetaldehyde (ACD) and tetrahydroisoquinolines (THIQs) in alcohol addiction. The overall hypothesis to be tested is that the formation of ACD and THIQs contribute to alcohol addiction. The goals of the present application are to examine the reinforcing effects of ACD and salsolinol (SAL) within the mesolimbic dopamine (DA) system of the rat. The following hypotheses will be tested in the present proposal: (a) ACID and SAL are reinforcing within the ventral tegmental area (VTA) of alcohol-preferring (P) rats; (b) SAL is reinforcing within the nucleus accumbens (NAC) shell of P rats; and (c) ACD and SAL potentiate ethanol reinforcement within the VTA of P rats. These hypotheses will be tested using the intracranial self-administration (ICSA) technique to examine the reinforcing actions of ACD and/or SAL within the VTA and/or NAC of P rats. Preliminary data indicate that female P rats self- administer 6 - 90 NM ACD directly into the posterior VTA. The present application will extend these findings using male P and Wistar rats. Specific aim 1 will examine the dose-response effects of ACD within the anterior VTA, as well as in regions adjacent to the VTA, to establish the site for the reinforcing effects of ACD. This aim will also examine extinction and reinstatement for the ICSA of ACD in the posterior VTA. In addition, specific aim 1 will compare the dose-response effects for the ICSA of ACD in the posterior VTA of P and Wistar rats. Specific aim 2 will examine the dose-response effects of SAL within the VTA and NAC of P rats. Specific aim 3 will examine the effects of ACD or SAL on the reinforcing effects of ethanol in the posterior VTA of P rats. In addition, this aim will examine whether conversion of ethanol to ACD may under- lie the ICSA of ethanol into the posterior VTA of P rats by co-infusing a catalase inhibitor with ethanol. The results of this study will provide information on the effects of ACD and SAL within the mesolimbic system, which could indicate a direct reinforcing effect of these compounds themselves and/or a potentiating effect of these compounds on the reinforcing properties of ethanol. Such results could provide valuable information on novel mechanisms underlying the addictive properties of alcohol and would provide a firm scientific foundation for future neurobiological studies.