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.
Highlights
THE ETHANOL MOLECULE Ethanol became part of our ecology over 200 million years ago when yeast started fermenting carbohydrates in fruits and grains, generating ethanol (Ratcliff et al, 2012)
To avoid a ceiling of the rewarding effect of acetaldehyde generated by catalase, animals were allowed access to 5% ethanol and water
It was postulated that if increases in ethanol intake induced by ALCOHOL DEPRIVATION EFFECT (ADE) were mediated by acetaldehyde, inhibition of ventral tegmental area (VTA) catalase synthesis by microinjection of an anticatalase lentiviral vector should inhibit ADE binge-drinking
Summary
Yedy Israel 1,2*, Mario Rivera-Meza 1, Eduardo Karahanian 3, María E. 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. Aversive is an increased acetaldehyde level resulting from the inhibition of liver aldehyde dehydrogenase-2 (ALDH2) synthesis (by an antisense coding gene against aldh mRNA). 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.
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