Ethanol as a Prodrug: Brain Metabolism of Ethanol Mediates Its Reinforcing Effects – A Commentary


Reprint requests: Richard A. Deitrich, PhD, Department of Pharmacology, School of Medicine, University of Colorado, Mail stop 8303, PO Box 6511, Aurora, CO 80045; Tel.: 303-724-3386; Fax: 303-724-3663;


Background:  This commentary discusses a study by Karahanian and colleagues (2011) on the role of central nervous system acetaldehyde in the reinforcing effects of ethanol. The goal is to emphasize the importance of the study and to discuss future directions.

Results:  This important paper solidifies the idea that the levels of acetaldehyde in the central nervous system have profound effects in mediating the reinforcing actions of ethanol. This is accomplished by manipulating the brain levels of acetaldehyde produced from ethanol by the injection of lentivirus containing either an anti-catalase shRNA construct or a rat liver alcohol dehydrogenase into the central nervous system and observing the effects on alcohol preference by high ethanol-consuming rats. A factor not directly considered is that acetaldehyde is further metabolized to acetate, which also has some behavioral actions.

Conclusions:  The efficacy of lentivirus injections of enzyme inhibitors or enzymes themselves to alter a behavioral response to ethanol is clearly demonstrated here. The many other actions of ethanol that are postulated to be a result of the production of acetaldehyde in the brain remain to be investigated by similar techniques. Possible “therapeutic avenues to reduce chronic alcohol use” are envisioned.