Flumazenil (Ro15-1788) does not affect ethanol tolerance and dependence.

There are conflicting reports concerning whether flumazenil (Ro15-1788) can antagonize the central effects of ethanol and ethanol withdrawal reactions. C57BL/6J mice were treated chronically with an ethanol liquid diet. Control mice were pair fed an isocaloric diet containing no ethanol.

The ability of chlordiazepoxide to maintain ethanol tolerance and dependence.

Two criteria need to be satisfied in the demonstration of cross-dependence to chlordiazepoxide (CDP) in ethanol-dependent mice. These are the ability of CDP to suppress ethanol withdrawal and to maintain the dependent state. In this study, mice which had been fed chronically an ethanol diet followed by two days of CDP diet treatment had more severe CDP withdrawal signs induced by Ro15-1788 than drug-naive mice which were similarly exposed to the CDP diet treatment.

Chronic treatment with ethanol or chlordiazepoxide alters the metabolism of chlordiazepoxide.

Although chronic ethanol administration in C57BL/6J mice did not cause an induction of ethanol metabolism, it altered the metabolism of chlordiazepoxide (CDP). Significantly lower blood levels of CDP, but higher levels of N-desmethyl CDP (NDCDP), were observed in ethanol-dependent mice compared to pair-fed controls during the first hour after CDP injection. Mice treated chronically with CDP showed significantly lower blood levels of CDP and NDCDP than pair-fed controls after a test dose of CDP.

Partial cross-dependence on ethanol in mice dependent on chlordiazepoxide.

Mice which had been fed chronically a liquid diet containing chlordiazepoxide (CDP) showed spontaneous and Ro15-1788-induced withdrawal signs upon CDP withdrawal. Ethanol (1.5 g/kg) injected 5 min before Ro15-1788 injection almost completely suppressed the withdrawal signs induced by the benzodiazepine receptor antagonist.

A liquid diet model of chlordiazepoxide dependence in mice.

Mice fed chronically (3 to 4 weeks) a liquid diet containing chlordiazepoxide (CDP) became physically dependent on the drug as demonstrated by the occurrence of withdrawal signs precipitated by injection of the benzodiazepine antagonist Ro15-1788 (5 to 25 mg/kg) or by omitting CDP from the diet (spontaneous withdrawal). Very low blood concentrations of CDP, but medium to high levels of the active metabolites N-desmethyl CDP and demoxepam were found during the period of CDP administration. The Ro15-1788-induced withdrawal signs appeared within 1 min after the injection of the antagonist and lasted for at least 10 min.

Transferrin and mitochondrial aspartate aminotransferase in young adult alcoholics.

Two recently proposed biochemical markers of alcoholism, namely, quantitation of plasma transferrin variant (Tf5.7) and the ratio of plasma mitochondrial aspartate aminotransferase (m-AspAT) to total AspAT (t-AspAT), were tested for their ability to detect young adult alcoholics. Another commonly used biochemical test, namely, activity of plasma gamma glutamyltransferase (GGT) was included as a comparison.

Does chronic ethanol intake confer full cross-tolerance to chlordiazepoxide?

Four behavioral tests, namely, hypothermia, horizontal dowel, runway and head-dipping, were used to assess tolerance to ethanol and cross-tolerance to chlordiazepoxide (CDP) in mice chronically treated with an ethanol diet for 15 days. Mice were tested on day 3 of ethanol withdrawal, with some being retested on day 8. In terms of hypothermia and the horizontal dowel test, ethanol tolerance conferred full cross-tolerance to CDP, but the conclusion based on results of the latter test may be equivocal.

Differential effects of Ro15-1788 in actions of chlordiazepoxide and ethanol.

Three behavioral tests, namely, runway activity, horizontal dowel test and hypothermia, were used to compare the effects of Ro15-1788, a specific benzodiazepine antagonist, on the common neuropharmacological actions of chlordiazepoxide (CDP) and ethanol in C57BL/6J mice. Ro15-1788 completely reversed the CDP-induced inhibition of runway activity and incoordination on a horizontal dowel, but only partially antagonized the hypothermic effects of CDP. The latter phenomenon was likely to be due to the rapid elimination of Ro15-1788, but could also be due to the fact that hypothermia might not be a specific action of CDP.

Substitution of chlordiazepoxide for ethanol in alcohol-dependent mice.

Alcohol dependence was induced in C57BL/6J mice by administration of a liquid diet containing ethanol. These mice showed alcohol withdrawal signs when the alcohol diet was withdrawn. However, when the alcohol diet was substituted with three liquid diets containing different amounts of chlordiazepoxide (CDP; 0.

Cross-tolerance between ethanol and chlordiazepoxide.

Drug-induced hypothermia was used to investigate drug tolerance and cross-tolerance. C57BL/6J mice, which were injected with a single dose of chlordiazepoxide (CDP; 30 mg/kg) one day before and reinjected with an equivalent dose of CDP the next day, did not develop tolerance to the drug. However, ethanol-pretreated (3.

Long-lasting reduction in ethanol selection after involuntary intake of ethanol/chlordiazepoxide.

C57BL/6J mice, after having been exposed to a free-choice condition between water and aqueous chlordiazepoxide (CDP, 25 mg/100 ml) or between water and ethanol/CDP, showed a significant trend for decreased preference for ethanol when tested 2 weeks later. Similarly, mice previously exposed to a no-choice intake of ethanol showed a significant decrease in ethanol preference when tested subsequently. A long-lasting (greater than 20 weeks) reduction in ethanol selection developed after mice were previously exposed to ethanol/CDP in a no-choice condition.

Influence of chlordiazepoxide on alcohol consumption in mice.

In a free-choice situation, chlordiazepoxide (CDP; 12.5 or 25 mg/100 ml; groups B or C), when incorporated in ethanol solutions (2 to 20%, v/v), caused a significant decrease in ethanol preference index (P.I.

Dissociation of tolerance and physical dependence after ethanol/chlordiazepoxide intake.

The previously-observed attenuation of withdrawal reactions in mice (group B) fed an ethanol diet containing chlordiazepoxide (CDP) was not due to a difference in the rate of disappearance of blood ethanol levels during chronic diet treatment in group B compared to mice which received only the ethanol diet (group A). Injection of group A mice with CDP or N-demethyl CDP (10 mg/kg) at the time of diet withdrawal did not result in any significant attenuation of withdrawal scores. Injection of the lactam metabolite of CDP (LCDP; 10 mg/kg) resulted in significantly attenuated withdrawal scores at 4 and 6 hr only, but the pattern of withdrawal scores were different from that for group B mice.

Alcohol withdrawal reactions after chronic intake of chlordiazepoxide and ethanol.

Withdrawal reactions were compared in C57BL/6J mice, which had been fed an ethanolic liquid diet containing chloridazepoxide (CDP, 3.2 or 6.4 mg/100 ml, group B or C, respectively) with those which had been administered an ethanol diet alone (group A) for 15 days.