Sergey M. Zimatkin

Ethanol metabolism in the brain

Acetaldehyde is suspected of being involved in the central mechanism of central nervous system depression and addiction to ethanol, but in contrast to ethanol, it can not penetrate easily from blood into the brain because of metabolic barriers. Therefore, the possibility of ethanol metabolism and acetaldehyde formation inside the brain has been one of the crucial questions in biomedical research of alcoholism. This article reviews the recent progress in this area and summarizes the evidence on the first stage of ethanol oxidation in the brain and the specific enzyme systems involved. The brain alcohol dehydrogenase and microsomal ethanol oxidizing systems, including cytochrome P450 II E1 and catalase are considered. Their physicochemical properties, the isoform composition, substrate specificity, the regional and subcellular distribution in CNS structures, their contribution to brain ethanol metabolism, induction under ethanol administration and the role in the neurochemical mechanisms of psychopharmacological and neurotoxic effects of ethanol are discussed. In addition, the nonoxidative pathway of ethanol metabolism with the formation of fatty acid ethyl esters and phosphatidylethanol in the brain is described.

OXIDATION OF ETHANOL TO ACETALDEHYDE IN BRAIN AND THE POSSIBLE BEHAVIORAL CONSEQUENCES

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).

Acetate-Dependent Mechanisms of Inborn Tolerance to Ethanol

AIMS To clarify the role of acetate in neurochemical mechanisms of the initial (inborn) tolerance to ethanol. METHODS Rats with low and high inborn tolerance to hypnotic effect of ethanol were used. In the brain region homogenates (frontal and parietal cortex, hypothalamus, striatum, medulla oblongata) and brain cortex synaptosomes, the levels of acetate, acetyl-CoA, acetylcholine (AcH), the activity of pyruvate dehydrogenase (PDG) and acetyl-CoA synthetase were examined. RESULTS It has been found that brain cortex of rats with high tolerance to hypnotic effect of ethanol have higher level of acetate and activity of acetyl-CoA synthetase, but lower level of acetyl-СCoA and activity of PDG. In brain cortex synaptosomes of tolerant rats, the pyruvate oxidation rate as well as the content of acetyl-CoA and AcH synthesis were lower when compared with intolerant animals. The addition of acetate into the medium significantly increased the AcH synthesis in synaptosomes of tolerant, but not of intolerant animals. Calcium ions stimulated the AcH release from synaptosomes twice as high in tolerant as in intolerant animals. Acetate eliminated the stimulating effect of calcium ions upon the release of AcH in synaptosomes of intolerant rats, but not in tolerant animals. As a result, the quantum release of AcH from synaptosomes in the presence of acetate was 6.5 times higher in tolerant when compared with intolerant rats. CONCLUSION The brain cortex of rats with high inborn tolerance to hypnotic effect of ethanol can better utilize acetate for the acetyl-CoA and AcH synthesis, as well as being resistant to inhibitory effect of acetate to calcium-stimulated release of AcH. It indicates the metabolic and cholinergic mechanisms of the initial tolerance to ethanol.

Influence of Chronic Alcohol Consumption on Histaminergic Neurons of the Rat Brain

AIMS To clarify the effect of chronic alcohol consumption on the brain histaminergic neurons in rats. METHODS Male Wistar rats were given 20% ethanol as the only source of drinking during 6 months, control rats had a free access to water. The samples of hypothalamus were prepared for light and electron microscopy accompanied by morphometry to examine the brain histaminergic neurons of E2 group. RESULTS Chronic ethanol consumption increased the amount of histologically abnormal forms of histaminergic neurons and decreased the whole amount of E2 histaminergic neurons (for 5%). The neuron bodies and nuclei increased in size and sphericity, the nuclear/cytoplasmic ratio decreased by 15%. The ultrastructural changes in histaminergic neurons demonstrate the activation of their nuclear apparatus, both destruction and hypertrophy and hyperplasia of organelles, especially lysosomes. Chronic ethanol consumption induces the disturbances in cytoplasmic enzymes of neurons: increases the activity of type B monoamine oxidase, dehydrogenases of lactate and NADH and, especially, marker enzyme of lysosomes acid phosphatase as well as inhibits the activity of dehydrogenases of succinate and glucose-6-phosphate. CONCLUSION Chronic alcohol consumption affects significantly the structure and metabolism of the brain histaminergic neurons, demonstrating both the neurotoxic effect of ethanol and processes of adaptation in those neurons, necessary for their survival.