Anxiogenic and stress-inducing effects of peripherally administered acetaldehyde in mice: Similarities with the disulfiram–ethanol reaction

Abstract

Peripheral accumulation of acetaldehyde, the first metabolite of ethanol, produces autonomic responses in humans called “flushing”. The aversive characteristics of flushing observed in some populations with an isoform of aldehyde dehydrogenase (ALDH2) less active, are the basis for treating alcoholics with disulfiram, an ALDH inhibitor. Although ethanol and centrally formed acetaldehyde have anxiolytic effects, peripheral accumulation of acetaldehyde may be aversive in part because it is anxiogenic. ObjectivesWe investigated the effect of direct administration of acetaldehyde on behavioral measures of anxiety and on hormonal markers of stress in mice. The impact of disulfiram on the anxiolytic actions of ethanol was evaluated. Acetate (a metabolite of acetaldehyde) was also studied. MethodsCD1 male mice received acetaldehyde (0, 25, 50, 75 or 100mg/kg) at different time intervals and were assessed in the elevated plus maze and in the dark–light box. Corticosterone release after acetaldehyde administration was also assessed. Additional experiments evaluated the impact of disulfiram on the anxiolytic effect of ethanol (0 or 1mg/kg), and the effect of acetate on the plus maze. ResultsDirect administration of acetaldehyde (100mg/kg) had an anxiogenic effect at 1, 11 or 26min after IP administration. Acetaldehyde was ten times more potent than ethanol at inducing corticosterone release. Disulfiram did not affect behavior on its own, but blocked the anxiolytic effect of ethanol at doses of 30 and 60mg/kg, and had an anxiogenic effect at the highest dose (90mg/kg) when co-administered with ethanol. Acetate did not affect any of the anxiety parameters. ConclusionsPeripheral administration or accumulation of acetaldehyde produces anxiogenic effects and induces endocrine stress responses. This effect is not mediated by its metabolite acetate.