Program of Molecular and Clinical Pharmacology, Faculty of Medicine, Institute of Biomedical Sciences, Santiago, Chile.
Alcohol Clin Exp Res. 2012 Mar;36(3):517-22. doi: 10.1111/j.1530-0277.2011.01606.x. Epub 2011 Sep 6.
In animal models of continuous alcohol self-administration, in which physical dependence does not constitute the major factor of ethanol intake, 2 factors likely contribute to the perpetuation of alcohol self-administration: (i) the rewarding effects of ethanol and (ii) the contextual conditioning cues that exist along with the process of self-administration. Present studies are aimed at understanding the relative contribution of these factors on the perpetuation of heavy alcohol self-administration, as an indication of relapse.
Wistar-derived UChB high ethanol drinker rats were allowed access to 10% ethanol and water on a 24-hour basis. In initial studies, an anticatalase shRNA gene-coding lentiviral vector aimed at inhibiting acetaldehyde generation was administered into the ventral tegmental area (VTA) of the animals prior to ethanol access. In subsequent studies, the lentiviral vector was administered to animals, which had consumed ethanol on a 24-hour basis, or a 1-hour basis, after the animals had reached high levels of ethanol intake for 60 to 80 days. In final studies, quinine (0.01%) was added to the ethanol solution to alter the conditioning taste/smell cues of alcohol that animals had chronically ingested.
Data indicate that the administration of an anticatalase vector into the VTA of naïve animals blocked reward and alcohol self-administration, while it was, nevertheless, inactive in inhibiting alcohol self-administration in rats that had been conditioned to ingest ethanol for over 2 months. The lack of inhibitory effect of the anticatalase vector on ethanol intake in animals that had chronically self-administered ethanol was fully reversed when the contextual conditioning cues of the alcohol solution were changed.
Data highlight the importance of conditioning factors in relapse and suggest that only abolishing or blunting it, along with long-lasting pharmacological treatment to reduce ethanol reward, may have protracted effects in reducing alcohol self-administration.
在连续酒精自我给药的动物模型中，由于身体依赖不是摄入乙醇的主要因素，有 2 个因素可能促成酒精自我给药的持续：（i）乙醇的奖赏效应和（ii）与自我给药过程同时存在的环境条件线索。目前的研究旨在了解这些因素对大量酒精自我给药持续的相对贡献，这是复发的一个指标。
允许 Wistar 衍生的 UChB 高乙醇饮用大鼠在 24 小时内接触 10%乙醇和水。在初步研究中，一种针对抑制乙醛生成的抗过氧化氢酶 shRNA 基因编码慢病毒载体在动物接触乙醇之前被递送到腹侧被盖区（VTA）。在随后的研究中，将慢病毒载体递送给已经连续 24 小时或 1 小时摄入乙醇的动物，此时动物已经达到了 60-80 天的高乙醇摄入量。在最后的研究中，将奎宁（0.01%）添加到乙醇溶液中，以改变动物长期摄入的酒精的条件味觉/气味线索。
数据表明，在 VTA 中给予抗过氧化氢酶载体可阻断奖赏和酒精自我给药，而在已经习惯摄入乙醇超过 2 个月的大鼠中，它不能抑制酒精自我给药。当改变酒精溶液的环境条件线索时，抗过氧化氢酶载体对慢性自我给予乙醇的动物的乙醇摄入量的抑制作用完全逆转。
数据强调了条件因素在复发中的重要性，并表明只有消除或削弱它，以及长期的药理学治疗以减少乙醇的奖赏，才能对减少酒精自我给药产生持久的影响。
