LAUSR

ABSTRACT A number of pre‐clinical studies have shown that brain‐generated acetaldehyde, the first metabolite of ethanol, exerts reinforcing effects that promote the acquisition of ethanol intake, while chronic intake maintenance appears to be mediated by alcohol‐induced brain neuroinflammation/oxidative stress. Recently, it was described that N‐(1,3‐benzodioxol‐5‐ylmethyl)‐2,6‐dichlorobenzamide (ALDA‐1) activates aldehyde dehydrogenase‐2 (ALDH2), enzyme that catalyzes the oxidation of ethanol‐derived acetaldehyde to acetate. The aim of this study was to determine the effects of ALDA‐1 on both the acquisition and the maintenance of alcohol intake in alcohol‐preferring UChB rats. For ethanol acquisition studies, naïve UChB rats were treated with five daily doses of ALDA‐1 (12.5, 25 or 50mg/kg, i.p.) from one day before the start of ethanol exposure. For chronic intake studies, UChB rats exposed for 98 days to a free access to 10% ethanol and water were treated daily with ALDA‐1 (12.5, 25 or 50mg/kg, i.p.) for five days. The administration of ALDA‐1 reduced by 72–90% (p<0.001) the acquisition of ethanol consumption in naïve rats. At chronic ethanol consumption, ALDA‐1 reduced ethanol intake by 61–82% (p<0.001). ALDA‐1 administration increased by 3‐ and 2.3‐fold the activity of ALDH2 in brain and liver, respectively. ALDA‐1 did not affect saccharin consumption, nor it modified the rate of ethanol elimination. The study shows that the activation of ALDH2 by ALDA‐1 is effective for inhibiting both the acquisition and the maintenance of chronic ethanol intake by alcohol‐preferring rats. Thus, the activation of brain ALDH2 may constitute a novel approach in the treatment of alcohol use disorders. HIGHLIGHTSALDA‐1 increased by 3‐fold the brain ALDH2 activity in rats.ALDA‐1 blocked the acquisition of ethanol intake.ALDA‐1 reduced by 61–82% chronic ethanol intake.ALDA‐1 did not modify voluntary saccharin consumption.ALDA‐1 did not change the rate of ethanol elimination.