Karahanian E1,2, Rivera-Meza M3, Quintanilla ME4, Muñoz D1, Israel Y4.
1Center for Biomedical Research, Fac. Health Sci., Universidad Autonoma de Chile, Santiago, Chile
2 Research Center for the Study of Alcohol Drinking Behavior in Adolescents, Universidad Autonoma de Chile, Santiago, Chile
3Dept. Pharmacol. & Toxicol. Chem., Fac. Chem. & Pharm. Sci., Universidad de Chile, Santiago, Chile
4Mol & Clin. Pharmacol. Program, ICBM-Fac. Medicine, Universidad de Chile, Santiago, Chile.
A wealth of evidence has accumulated that shows that ethanol derived brain-generated acetaldehyde is a rewarding molecule while acetaldehyde generated in the liver is aversive when elevated in the periphery. Disulfiram a drug that inhibits ALDH2, both in brain and liver, is inactive in reducing ethanol intake in animals that have ingested ethanol chronically. These data in animals are in line with placebo-controlled clinical studies that show that in alcoholics disulfiram does not exceed the anti-alcohol effects of placebo. In animals that have consumed ethanol chronically, a liver-specific antisense drug against aldehyde dehydrogenase-2 (ALDH2) that does not penetrate the brain markedly reduces the activity of the enzyme, greatly increases blood acetaldehyde and lowers ethanol intake. Ideally, a clinically available drug acting primarily in the periphery should be sought to increase acetaldehyde levels and generate an aversion to ethanol. We show that the administration of fenofibrate, a drug used in the treatment of hypertriglyceridemia, elevates liver catalase, markedly increases acetaldehyde levels and generates a strong aversion against voluntary ethanol consumption in rats that have ingested alcohol chronically. Clinical studies by groups in the United States are presently undergoing to determine the effectiveness of fenofibrate as a treatment of alcoholism.
This work was supported by Fondecyt Grant #1150850 and Conicyt ACT1411.