Mouse Model Of Binge Drinking Research Articles

Thymic Atrophy Caused by Ethanol in a Mouse Model for Binge Drinking: Involvement of Endogenous Glucocorticoids

Consumption of large amounts of ethanol (EtOH) in a single drinking episode is common, but very little is known about the immunological effects of such occurrences. Exposure to EtOH for several days is immunosuppressive in rodent models, and a single dose of EtOH causes substantial increases in endogenous glucocorticoid levels which might have immunosuppressive effects. In the present study, the effects of a single dose of EtOH on the thymus and the role of endogenous glucocorticoids in these effects were examined in B6C3F1 female mice. A single dose of EtOH decreased thymus weight and cellularity, predominantly by elimination of CD4 +CD8 + (immature) thymocytes. This occurred over a broad range of EtOH doses and was associated with behavioral effects (ranging from mild ataxia to unresponsiveness) similar to those noted in human binge drinkers. Several lines of evidence indicate that the effects of EtOH on the thymus are mediated by endogenous glucocorticoids: (1) corticosterone levels in EtOH-treated mice increased more than 10-fold and remained significantly elevated for up to 12 hr; (2) the most glucocorticoid-sensitive thymocytes (CD4 +CD8 + cells) were preferentially depleted by EtOH; (3) before thymocyte depletion was evident, substantial DNA fragmentation occurred in the thymus as would be expected in the case of glucocorticoid-induced apoptosis: (4) the glucocorticoid antagonist, RU 486, blocked thymic atrophy and DNA fragmentation in EtOH treated mice; (5) EtOH and its major metabolites at concentrations comparable to or greater than expected in vivo did not decrease thymocyte viability in 20-hr cultures, indicating that direct action of EtOH or its metabolites on thymocytes does not play an important role in EtOH-induced thymic atrophy. These results suggest that a single dose of EtOH induces thymic atrophy which is predominantly mediated by increased levels of endogenous glucocorticoids. The mouse model described here should be useful in evaluating other effects of binge drinking on the immune system, and the experimental strategy described should be applicable in investigating the role of endogenous glucocorticoids in thymic atrophy induced by other chemicals and drugs.

Aspirin pretreatment reduces ethanol withdrawal severity in a mouse model of binge drinking

Nonsteroidal antiinflammatory drugs (NSAIDs) such as aspirin, ibuprofen, and indomethacin, which inhibit prostaglandin (PG) synthesis, have a pronounced effect on a broad range of ethanol (EtOH) actions. Given this, it is somewhat surprising that NSAID treatment has not been found to alter major signs of ethanol withdrawal. To date, the only effect found has been indirect, that is, NSAID treatment reduces the efficacy of PG precursor administration in the treatment of ethanol withdrawal via the inhibition of PG formation. However, in those studies reporting negative results NSAID administration was delayed until EtOH withdrawal. Studies demonstrating NSAID-related attenuation of other actions of EtOH have typically employed a pretreatment paradigm in which NSAIDs are administered prior to, not after, ethanol exposure. Thus, it may be that the point in the ethanol exposure/withdrawal episode at which NSAIDs are administered could be crucial in determining their effects of the ethanol withdrawal syndrome. To address this issue, we employed a multiple-exposure “binge drinking” model. On each of 6 treatment days, male BALB/c mice were injected subcutaneously with either acetylsalicylic acid (ASA, 150 mg/kg) or the buffer vehicle, followed 1 h later by either ethanol (4.0 g/kg) or saline (0.9%) by gavage. Ethanol withdrawal severity, as measured by handling-induced convulsions, was determined 2, 4, 6, 8, 10, 12, and 24 h after EtOH gavage. ASA pretreatment was found to significantly reduce handling-induced convulsions in ethanol-intubated animals. In fact, the attenuation was of such a magnitude that the ASA-pretreated ethanol group did not significantly differ in withdrawal severity from non-ethanol-exposed controls. This effect was not likely due to ASA-related alterations in ethanol pharmacokinetics. These findings have relevance for the understanding of the basic mechanisms underlying ethanol dependence, as well as the potential role of PGs in this phenomenon.