Oxidation of ethanol to acetaldehyde in brain and the possible behavioral consequences.

Abstract

One of the oldest theories of ethanol’s action is that the first metabolite, acetaldehyde, is responsible for some of the actions in the central nervous system (Hunt, 1996; Hashimoto et a1. 1989; Tan et a1. 1993; Bergamaschi et a1. 1988; Zimatkin and Deitrich, 1997; Thadani and Truitt, 1977; Collins et al. 1988; Heap et al. 1995). This hypothesis fell into disfavor for a number of reasons. The first was that following ethanol ingestion, the blood levels of acetaldehyde are extremely low, provided that the artifactual formation of acetaldehyde is accounted for (Sippel, 1974; Westcott et a1. 1980; Sippel and Eriksson, 1975; Tabakoff et a1. 1976; Zimatkin and Pronko, 1995). The levels in normal humans are nearly undetectable in the blood, of the order of 1 μM. The second problem was that even if the blood acetaldehyde levels were significant, the molecule does not seem to be able to penetrate the blood brain barrier because of the presence of aldehyde dehydrogenase in blood vessels. Substantial blood levels were required before acetaldehyde appeared in the brain (Westcott et a1. 1980; Tabakoff et al. 1976; Sippel and Eriksson, 1975; Sippel, 1974; Sippel, 1974). A third issue was that one could inhibit the oxidation of ethanol to acetaldehyde with pyrazole but intoxication still ensued. Indeed the use of pyrazole was critical in the vapor chamber method of Goldstein where ethanol metabolism was slowed in order to physically addict mice to ethanol (Goldstein and Pal, 1971).