Diana Marco, Peana Alessandra Tiziana, Sirca Donatella, Lintas Alessandra, Melis Miriam, Enrico Paolo
"G. Minardi" Laboratory of Cognitive Neurosciences, Department of Drug Sciences, University of Sassari, Sassari, Italy.
Ann N Y Acad Sci. 2008 Oct;1139:307-17. doi: 10.1196/annals.1432.009.
Ethyl alcohol (EtOH), the main psychoactive ingredient of alcoholic drinks, is widely considered responsible for alcohol abuse and alcoholism through its positive motivational properties, which depend, at least partially, on the activation of the mesolimbic dopaminergic system. On the other hand, acetaldehyde (ACD), EtOH's first metabolite, has been classically considered aversive and useful in the pharmacologic therapy of alcoholics. Here we show that EtOH-derived ACD is necessary for EtOH-induced place preference, a preclinical test with high predictive validity for reward liability. We also found that ACD is essential for EtOH-increased microdialysate dopamine (DA) levels in the nucleus accumbens (NAcc), and that this effect is mimicked by ACD administration to the intraventral tegmental area (VTA). Furthermore, in vitro, ACD enhances VTA DA neuronal firing. Coherently, EtOH-stimulating properties on DA neurons are prevented by pharmacologic blockade of local catalase: the main metabolic step for biotransformation of EtOH into ACD in the central nervous system. These results provide in vivo and in vitro evidence for a key role of ACD in EtOH motivational properties and its activation of the mesolimbic DA system. Additionally, these observations suggest that ACD, by increasing VTA DA neuronal activity, would oppose its well-known peripherally originating aversive properties. These findings could help in devising new effective pharmacologic therapies in alcoholism.
乙醇（EtOH）是酒精饮料中的主要精神活性成分，因其具有积极的动机特性而被广泛认为是导致酒精滥用和酒精成瘾的原因，这种动机特性至少部分取决于中脑边缘多巴胺能系统的激活。另一方面，乙醇的首个代谢产物乙醛（ACD）传统上被认为具有厌恶作用，可用于酒精成瘾者的药物治疗。在此，我们表明乙醇衍生的乙醛对于乙醇诱导的位置偏爱是必需的，位置偏爱是一种对奖赏倾向具有高预测效度的临床前测试。我们还发现，乙醛对于乙醇增加伏隔核（NAcc）中的微透析多巴胺（DA）水平至关重要，并且向腹侧被盖区（VTA）注射乙醛可模拟这种效应。此外，在体外，乙醛可增强VTA多巴胺能神经元的放电。连贯地，通过对局部过氧化氢酶进行药理学阻断可阻止乙醇对多巴胺能神经元的刺激特性：过氧化氢酶是中枢神经系统中将乙醇生物转化为乙醛的主要代谢步骤。这些结果提供了体内和体外证据，证明乙醛在乙醇的动机特性及其对中脑边缘多巴胺能系统的激活中起关键作用。此外，这些观察结果表明，乙醛通过增加VTA多巴胺能神经元的活性，会与其众所周知的外周起源的厌恶特性相反。这些发现可能有助于设计新的有效的酒精成瘾药物治疗方法。
