Individuals who carry the most active alcohol dehydrogenase (ADH) isoforms are protected against alcoholism. This work addresses the mechanism by which a high ADH activity leads to low ethanol intake in animals. Male and female ethanol drinker rats (UChB) were allowed access to 10% ethanol for 1 h. Females showed 70% higher hepatic ADH activity and displayed 60% lower voluntary ethanol intake than males. Following ethanol administration (1 g/kg ip), females generated a transient blood acetaldehyde increase ("burst") with levels that were 2.5-fold greater than in males (P Ͻ 0.02). Castration of males led to 1) an increased ADH activity (ϩ50%, P Ͻ 0.001), 2) the appearance of an acetaldehyde burst (3-to 4-fold vs. sham), and 3) a reduction of voluntary ethanol intake comparable with that of naïve females. The ADH inhibitor 4-methylpyrazole blocked the appearance of arterial acetaldehyde and increased ethanol intake. Since the release of NADH from the ADH ⅐ NADH complex constitutes the rate-limiting step of ADH (but not of ALDH2) activity, endogenous NADH oxidizing substrates present at the time of ethanol intake may contribute to the acetaldehyde burst. Sodium pyruvate given at the time of ethanol administration led to an abrupt acetaldehyde burst and a greatly reduced voluntary ethanol intake. Overall, a transient surge of arterial acetaldehyde occurs upon ethanol administration due to 1) high ADH levels and 2) available metabolites that can oxidize hepatic NADH. The acetaldehyde burst is strongly associated with a marked reduction in ethanol intake. male; female; orchidectomy; arterial; pyruvate; limited access ETHANOL IS METABOLIZED IN THE LIVER by alcohol dehydrogenase (ADH) into acetaldehyde, a metabolite that is subsequently oxidized into acetate by aldehyde dehydrogenase (ALDH2). Humans who carry a dominant negative mutation of the gene that codes for mitochondrial aldehyde dehydrogenase (33) display a marked elevation in blood acetaldehyde levels following ethanol intake, which curtails further alcohol use (15). Individuals carrying this allele (ALDH2*2) are protected by 66 to 99% against alcohol abuse and alcoholism (7,8,30,31). Although it has been suggested that acetaldehyde generated in the brain may be a rewarding metabolite (20), high levels of blood acetaldehyde are aversive, as shown by the marked inhibition of ethanol intake in animals in which peripheral ALDH2 activity is reduced and blood acetaldehyde levels are increased by antisense drugs that do not penetrate the bloodbrain barrier (6).Individuals carrying an ADH allele (ADH1B*2) that codes for an isoform that is one order of magnitude more active than that coded by the usual ADH1B*1 (9) are also protected against heavy alcohol use and alcoholism (26; see also meta-analysis, Ref. 34). The highly active ADH is found in some East Asians and Ashkenazi Jews. The steady-state rate of ethanol metabolism in individuals carrying the ADH1B*2 allele is only 8 -13% greater than that of subjects carrying ADH1B*1 (18), indicating that in humans the maxima...