PubMed · 10291561
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B E Brody. EAPs: past, present, and future.. https://pubmed.ncbi.nlm.nih.gov/10291561/
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Elevation of serum interleukin-6 (IL-6) levels is always associated with alcoholic liver disease (ALD), but the significance of such elevation is not clear. Here we show that chronic ethanol consumption induces significant apoptosis in the liver of IL-6 (-/-) mice but not IL-6 (+/+) mice. IL-6 (-/-) hepatocytes are more susceptible to ethanol- and tumor necrosis factor alpha- (TNFalpha-) induced apoptotic killing, which can be corrected by IL-6. Expression of both anti-apoptotic (such as Bcl-2 and Bcl-x(L)) and proapoptotic (such as Bax) proteins is markedly elevated in the liver of human ALD and chronically ethanol-fed IL-6 (+/+) mice. On the contrary, induction of Bcl-2 and Bcl-x(L) is not observed in the liver of chronically ethanol-fed IL-6 (-/-) mice, whereas expression of Bax protein remains elevated. Injection of IL-6 markedly induces expression of Bcl-2 and Bcl-x(L) but not Bax in the liver. Finally, high concentrations of ethanol inhibit IL-6-activated anti-apoptotic signal, but increasing the concentrations of IL-6 is able to overcome such inhibitory effect. These findings suggest that elevated serum IL-6 levels in ALD may overcome the inhibitory effect of ethanol on IL-6-mediated anti-apoptotic signals and prevent alcohol-induced hepatic apoptosis by induction of Bcl-2 and Bcl-x(L).
The relationship between years of excessive alcohol consumption and central serotonergic neurotransmission, as assessed by the prolactin (PRL) response to D-fenfluramine, was investigated in 22 male alcohol-dependent subjects. A negative correlation was obtained, that is, the longer duration of excessive alcohol consumption the lower PRL response to D-fenfluramine. It is therefore suggested that long duration of excessive alcohol consumption in alcohol-dependent subjects causes a reduction in central serotonergic neurotransmission, possibly by a toxic effect of alcohol on serotonin neurons. The relationship between depressive and anxiety symptoms during on-going drinking and the PRL response to D-fenfluramine was also investigated. No such correlations were obtained, suggesting that reduction in central serotonergic neurotransmission does not pre-dispose to the development of depressive and anxiety symptoms, at least in relation to on-going drinking in alcohol-dependent subjects.
UNLABELLED: Serotonergic abnormalities may be present in individuals with either substance dependence (SD) or antisocial personality disorder (ASPD), disorders that occur together commonly. Consequently, genes encoding serotonin (5-HT) receptors are candidates for genetic studies of both disorders. found evidence for linkage of antisocial alcoholism to HTR1B (the locus encoding the 5-HT1B receptor) in both Finns and Southwestern American Indians, and of allelic association of a G861C polymorphism at that locus with antisocial alcoholism in Finns. Unless the G861C polymorphism is found to be functional, it must be in linkage disequilibrium (LD) with a functional variant for it to be of physiological significance. METHODS: The present study evaluated LD across three polymorphic systems at HTR1B and haplotype frequencies and allelic association of these systems with both SD generally and alcohol dependence (AD) specifically, with or without a comorbid antisocial diagnosis. Subjects were 370 European Americans (EAs) and 123 African Americans (AAs). RESULTS: Although there was strong evidence for LD across polymorphic systems in both populations, there was no evidence for association to SD or AD, either alone or with a comorbid antisocial diagnosis. CONCLUSION: Despite no evidence in this study for allelic association of HTR1B to antisocial substance dependence, further evaluation of the hypothesized association is warranted in other population groups.