Ethanol as a Prodrug: Brain Metabolism of Ethanol Mediates its Reinforcing Effects

被引:86
|
作者
Karahanian, Eduardo [2 ]
Quintanilla, Maria Elena
Tampier, Lutske
Rivera-Meza, Mario [3 ,4 ]
Bustamante, Diego
Gonzalez-Lira, Victor
Morales, Paola
Herrera-Marschitz, Mario
Israel, Yedy [1 ,3 ,4 ,5 ]
机构
[1] Univ Chile, Inst Biomed Sci, Fac Med, Lab Gene Therapy,Program Mol & Clin Pharmacol, Santiago, Chile
[2] Univ Diego Port, Ctr Biomed Res, Fac Med, Santiago, Chile
[3] Univ Chile, Dept Pharmacol & Toxicol Chem, Fac Chem & Pharmaceut Sci, Santiago, Chile
[4] Univ Chile, Inst Cell Dynam & Biotechnol, Santiago, Chile
[5] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA
关键词
Alcoholism; Lentiviral Vector; Brain Catalase; Acetaldehyde; Microdialysis; Reinforcement; VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS; DOPAMINE RELEASE; ACETALDEHYDE; CATALASE; INVOLVEMENT; GENE; RATS; UCHA; CONSUMPTION;
D O I
10.1111/j.1530-0277.2011.01439.x
中图分类号
R194 [卫生标准、卫生检查、医药管理];
学科分类号
摘要
Background: While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known, that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors, one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase (ADH), to respectively inhibit or increase brain acetaldehyde synthesis. Methods: The lentiviral vectors, which incorporate the genes they carry into the cell genome, were (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water. Results: Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (-94%p < 0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for ADH greatly stimulated (2 to 3 fold p < 0.001) their voluntary ethanol consumption. Conclusions: The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.
引用
收藏
页码:606 / 612
页数:7
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