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Alcohol Action (alcohol + action)
Selected AbstractsAlcohol potentiates hepatitis C virus replicon expressionHEPATOLOGY, Issue 1 2003Ting Zhang Alcohol consumption accelerates liver damage and diminishes the anti-hepatitis C virus (HCV) effect of interferon alfa (IFN-,) in patients with HCV infection. It is unknown, however, whether alcohol enhances HCV replication and promotes HCV disease progression. The availability of the HCV replicon containing hepatic cells has provided a unique opportunity to investigate the interaction between alcohol and HCV replicon expression. We determined whether alcohol enhances HCV RNA expression in the replicon containing hepatic cells. Alcohol, in a concentration-dependent fashion, significantly increased HCV replicon expression. Alcohol also compromised the anti-HCV effect of IFN-,. Investigation of the mechanism(s) responsible for the alcohol action on HCV replicon indicated that alcohol activated nuclear factor ,B (NF-,B) promoter. Caffeic acid phenethyl ester (CAPE), a specific inhibitor of the activation of NF-,B, abolished alcohol-induced HCV RNA expression. In addition, naltrexone, an opiate receptor antagonist, abrogated the enhancing effect of alcohol on HCV replicon expression. In conclusion, alcohol, probably through the activation of NF-,B and the endogenous opioid system, enhances HCV replicon expression and compromises the anti-HCV effect of IFN-,. Thus, alcohol may play an important role in vivo as a cofactor in HCV disease progression and compromise IFN-,-based therapy against HCV infection. [source] Effects of Straight Chain Alcohols on Specific Isoforms of Adenylyl CyclaseALCOHOLISM, Issue 4 2010Mohammad Hasanuzzaman Background:, Our previous studies showed that the activity of adenylyl cyclase (AC) was enhanced by pharmacologically relevant concentrations of ethanol, that this enhancing effect of ethanol on AC activity was AC isoform specific, and that the alcohol cutoff effect for n -alkanol potentiation of AC activity was also AC isoform specific. Therefore, we hypothesized that within the cyclic AMP-generating system, AC is the target of ethanol's action and that alcohols interact directly with the AC molecules. To characterize the interaction between alcohols and AC proteins, the effects of a series of straight chain alcohols would be very valuable in understanding alcohol action at the molecular level. To our knowledge, straight chain alcohols other than n- alkanols and 1,,-diols have not been used extensively to study alcohol effects on the activity of AC or other proteins important in the alcohol research field. Methods:, The effects of a series of straight chain alcohols on D1A dopamine receptor-stimulated activity of AC isoforms type 6, 7, and 9 (AC6, AC7, and AC9) were examined in transfected Hela cells by a cAMP accumulation assay. Results:, In general, all 3 AC isoforms responded to a series of straight chain alcohols in a similar manner. The order of responsiveness is as follows: monoalcohol > diol > triol and tetraol. Within monoalcohols, 1-alcohols had larger effects than 2-alcohols. Two of 3 stereoisomers of 2,3-butanediol, [D-(-)-2,3-butanediol and meso -2,3-butanediol] showed similar enhancing effects on all 3 AC isoforms. However, the third stereoisomer, L-(+)-2,3-butanediol, inhibited AC7 activity, while it stimulated AC6 and AC9. Conclusion:, The number and the position of hydroxyl groups in straight chain alcohols play an important role in the magnitude of the enhancement on AC activity. Regardless of AC isoforms, the most effective of the straight chain alcohols seems to be the 1-alcohol (n -alkanol) for a given chain length. We found that one of the stereoisomers of 2,3-butanediol had opposite effects on AC activity depending on the AC isoform. Overall, the results are consistent with the hypotheses and demonstrate that a series of straight chain alcohols can be a valuable tool to study AC-alcohol interactions. [source] Ethanol-induced elevation of 3,-hydroxy-5,-pregnan-20-one does not modulate motor incoordination in ratsALCOHOLISM, Issue 8 2004Rahul T. Khisti Background: Ethanol administration elevates the levels of GABAergic neuroactive steroids in brain and contributes to some of its behavioral actions. In the present study, we investigated whether such elevation of GABAergic neuroactive steroids contributes to the motor incoordinating effects of ethanol. Methods: Sprague-Dawley rats were administered ethanol (2 g/kg intraperitoneally) or saline, and the level of 3,-hydroxy-5,-pregnan-20-one (3,,5,-THP) was measured across time in cerebral cortex and in various brain regions at the peak time by radioimmunoassay. To study whether increases in GABAergic neuroactive steroids are responsible for the motor incoordinating actions of ethanol, rats were subjected to chemical (5,-reductase inhibitor, finasteride) and surgical (adrenalectomy) manipulations before receiving ethanol (2 g/kg intraperitoneally) injections. The rats were then subjected to different paradigms to evaluate motor impairment including the Majchrowicz motor intoxication rating scale, Rotarod test, and aerial righting reflex task at different time points. Results: The radioimmunoassay of 3,,5,-THP in different brain regions showed that ethanol increases 3,,5,-THP levels by 3- and 9-fold in cerebral cortex and hippocampus, respectively. There was no change in 3,,5,-THP levels in cerebellum and midbrain. The time course of 3,,5,-THP elevations in the cerebral cortex showed significant increases 20-min after ethanol injection with a peak at 60 min. In contrast, motor toxicity peaked between 5 and 10 min after ethanol injections and gradually decreased over time. Furthermore, adrenalectomy or pretreatment with finasteride (2 × 50 mg/kg, subcutaneously) did not reduce motor incoordinating effects of ethanol as assessed by the Majchrowicz intoxication rating score, Rotarod test, or aerial righting reflex task. Conclusions: Ethanol increases GABAergic neuroactive steroids in a time- and brain region-selective manner. The role of neuroactive steroids in alcohol action is specific for certain behaviors. Alcohol-induced deficits in motor coordination are not mediated by elevated neuroactive steroid biosynthesis. [source] Acetylcholine and Alcohol Sensitivity of Neuronal Nicotinic Acetylcholine Receptors: Mutations in Transmembrane DomainsALCOHOLISM, Issue 12 2002Cecilia M. Borghese Background The effect of n-alcohols on glycine and ,-aminobutyric acid type A receptors depends on two specific amino acids (AAs) located in the transmembrane domains (TM) 2 and 3. Our aim was to assess whether the corresponding AAs in the neuronal nicotinic acetylcholine receptor (nAChR) also formed a binding pocket for alcohols. Methods We made single AA substitutions in the homologous sites in rat neuronal nAChR ,2 and ,4 (,L261 and ,L283) and expressed them in Xenopus laevis oocytes in combination with ,4 wild type. The effect of different n-alcohols was studied in ,4(L261A),4 and ,4(L283A),4 nAChRs. The effect of ethanol, propanol, and octanol on acetylcholine (ACh) responses was studied in ,2(L261X),4 and ,2(L283X),4 nAChRs. Results Most of the mutations in the ,2 subunit, in either the 261 or the 283 position, induced changes in ACh sensitivity and increased alcohol action, but none was able to reduce ethanol potentiation. In ,4(L283A),4, enhancement of potentiation by short-chain alcohols was observed, as well as a change from inhibition to potentiation for long-chain alcohols. The exposure of the AAs was assessed through the action of a charged thiol-specific reagent on ,2(L261C),4 and ,2(L283C),4, and these experiments suggest that the AA in TM2 is located in a water-accessible position, whereas the AA in TM3 is inaccessible. However, a noncharged thiol-specific reagent did not affect either ACh responses or ethanol effect on ,2(L261C),4. Conclusions The AAs located at positions 261 and 283 of the ,2 and ,4 nAChR subunits do not seem to form a binding pocket for alcohols. Additional studies are required to determine whether alcohols act on a site near these AAs or on sites unrelated to the TM2-TM3 site found in glycine and ,-aminobutyric acid type A receptors. [source] Possible Pleiotropic Effects of Genes Specifying Sedative/Hypnotic Sensitivity to Ethanol on Other Alcohol-Related TraitsALCOHOLISM, Issue 10 2002Jeremy C. Owens Background Initial sensitivity to ethanol is a predictor of alcohol abuse that has been studied extensively in both human and animal populations. Selection for initial sensitivity to the sedative/hypnotic effects of ethanol resulted in the long-sleep and short-sleep lines of mice. Some of the genes selected in these lines could also specify differential responses in other ethanol-related phenotypes and, perhaps, for other drugs of abuse. We assessed congenic mice carrying a single quantitative trait locus (QTL) from the inbred long-sleep (ILS) or inbred short-sleep (ISS) strain on the reciprocal background for a number of ethanol- and pentobarbital-related phenotypes. Methods Each congenic strain was tested for ethanol elimination rates at 4.1 g/kg, ethanol-induced ataxia at 2.0 g/kg, ethanol-induced hypothermia at 4.1 g/kg, and pentobarbital-induced loss of righting reflex (LORR) at 60 mg/kg. Additionally, the ILS.ISS congenics were tested for low-dose ethanol-induced activation (LDA) at five doses ranging from 0.6 to 1.2 g/kg ethanol, and the ISS.ILS congenics were tested for LDA at 1.8 g/kg of ethanol. Results There was little difference in the ethanol elimination rate between congenics and background strains, although a modest sex effect was found, with the females eliminating ethanol more rapidly than the males. We were unable to replicate previous differences found in LDA for the Lore1 congenic on the ISS background, because none of the congenics differed from controls for LDA. Lore5 congenics showed a differential effect of pentobarbital-induced LORR in the expected directions. The Lore1 congenics on the ISS background showed more ethanol-induced ataxia than the ISS controls. Additionally, the hypothermic response seems affected by Lore4 and Lore5 and maybe others. Conclusions At least two regions carrying a QTL specifying sensitivity to high doses of ethanol cospecify altered sensitivity in other measures of alcohol action. Specifically, these QTLs clearly affect ethanol-induced hypothermia and pentobarbital-induced LORR and possibly ethanol-induced ataxia. [source] Ethanol Enhances Taurine-Activated Glycine Receptor FunctionALCOHOLISM, Issue 9 2010Brian T. Welsh Background:, Emerging evidence suggests that taurine acts as a partial agonist on glycine receptors (GlyR) in vitro and in vivo. Ethanol acts as an allosteric modulator on the GlyR producing a leftward shift of the glycine concentration,response curve, with no enhancing effects observed at saturating glycine concentrations. However, to date, no electrophysiological studies have been performed on ethanol modulation of taurine-activated GlyR. Methods:, Wild-type ,1 GlyR, or those bearing a serine-267 to isoleucine replacement (S267I), were homomerically expressed in Xenopus oocytes and voltage clamped at ,70 mV. Ethanol was co-applied with varying concentrations of glycine or taurine and the enhancing effects of ethanol compared. Results:, Ethanol potentiated glycine- and taurine-activated GlyR responses in a concentration-dependent manner. It shifted taurine and glycine concentration,response curves to the left, having no effects at saturating agonist concentrations. Chelation of zinc by tricine decreased ethanol enhancement of taurine-gated GlyR function. The S267I mutation prevented ethanol enhancement of taurine-mediated responses as previously also reported for glycine. Conclusion:, Ethanol modulates taurine activation of GlyR function by a mechanism similar to that of the full agonist glycine. The lack of effect of ethanol at saturating taurine concentrations provides mechanistic information on alcohol actions at the GlyR. [source] | ||||||||||