PubMed · 10242186
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1979-05-15. Special program meets special needs.. https://pubmed.ncbi.nlm.nih.gov/10242186/
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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.
Activation of Kupffer cells by lipopolysaccharide (LPS) is a critical step in the pathogenesis of alcoholic liver disease. Kupffer cells isolated from rats fed ethanol in their diet for 4 wk accumulated 4.3-fold more tumor necrosis factor (TNF)-alpha in response to LPS compared with pair-fed rats. In contrast, LPS-stimulated interleukin (IL)-1 accumulation was 50% lower after ethanol feeding. LPS-stimulated TNF-alpha mRNA accumulation was twofold higher after ethanol feeding, whereas IL-1beta mRNA accumulation was blunted. To understand the mechanisms for this differential response, we investigated the effects of ethanol on LPS-dependent signal transduction. Chronic ethanol feeding increased LPS-stimulated extracellular receptor-activated kinases 1/2 (ERK1/2) activation. Activation of ERK1/2 was required for maximal increases in TNF-alpha and IL-1beta mRNA and was associated with increased binding of early growth response-1 (Egr-1) to the TNF-alpha promoter after ethanol feeding. In contrast, ethanol feeding completely abrogated activation of nuclear factor-kappaB DNA-binding activity by LPS and had no effect on AP-1 binding. Together, these data suggest that enhanced activation of ERK1/2 and Egr-1 contributes to increased TNF-alpha production after chronic ethanol feeding.