title: Gene specific modifications unravel ethanol and acetaldehyde actions.
abstract: Ethanol is metabolized into acetaldehyde mainly by the action of alcohol dehydrogenase in the liver, while mainly by the action of catalase in the brain. Aldehyde dehydrogenase-2 metabolizes acetaldehyde into acetate in both organs. Gene specific modifications reviewed here show that an increased liver generation of acetaldehyde (by transduction of a gene coding for a high-activity liver alcohol dehydrogenase ADH1(*)B2) leads to increased blood acetaldehyde levels and aversion to ethanol in animals. Similarly aversive is an increased acetaldehyde level resulting from the inhibition of liver aldehyde dehydrogenase-2 (ALDH2) synthesis (by an antisense coding gene against aldh2 mRNA). The situation is diametrically different when acetaldehyde is generated in the brain. When the brain ventral tegmental area (VTA) is endowed with an increased ability to generate acetaldehyde (by transfection of liver rADH) the reinforcing effects of ethanol are increased, while a highly specific inhibition of catalase synthesis (by transduction of a shRNA anti catalase mRNA) virtually abolishes the reinforcing effects of ethanol as seen by a complete abolition of ethanol intake in rats bred for generations as high ethanol drinkers. Data shows two divergent effects of increases in acetaldehyde generation: aversive in the periphery but reinforcing in the brain.
authors.affiliation: Faculty of Medicine, Molecular and Clinical Pharmacology Program, University of Chile Santiago, Chile ; Department of Pharmacological and Toxicological Chemistry, University of Chile Santiago, Chile.
authors.forename: Yedy
authors.initials: Y
authors.lastname: Israel
authors.forename: Mario
authors.initials: M
authors.lastname: Rivera-Meza
authors.forename: Eduardo
authors.initials: E
authors.lastname: Karahanian
authors.forename: María E
authors.initials: ME
authors.lastname: Quintanilla
authors.forename: Lutske
authors.initials: L
authors.lastname: Tampier
authors.forename: Paola
authors.initials: P
authors.lastname: Morales
authors.forename: Mario
authors.initials: M
authors.lastname: Herrera-Marschitz
keywords: alcohol dehydrogenase; aldehyde dehydrogenase; aversion; catalase; reinforcement