Abstract
Alcohol (ethanol) is widely consumed for its desirable effects but unfortunately has strong addiction potential. Some imidazobenzodiazepines such as Ro15-4513 are able to antagonize many ethanol-induced behaviors. Controversial biochemical and pharmacological evidence suggest that the effects of these ethanol antagonists and ethanol are mediated specifically via overlapping binding sites on α4/δ-containing GABAA-Rs. To investigate the requirement of α4-containing GABAA-Rs in the mechanism of action of Ro15-4513 on behavior, wildtype (WT) and α4 knockout (KO) mice were compared for antagonism of ethanol-induced motor incoordination and hypnosis. Motor effects of ethanol were tested in two different fixed speed rotarod assays. In the first experiment, mice were injected with 2.0 g/kg ethanol followed 5 min later by 10 mg/kg Ro15-4513 (or vehicle) and tested on a rotarod at 8 rpm. In the second experiment, mice received a single injection of 1.5 g/kg ethanol ± 3 mg/kg Ro15-4513 and were tested on a rotarod at 12 rpm. In both experiments, the robust Ro15-4513 antagonism of ethanol-induced motor ataxia that was observed in WT mice was absent in KO mice. A loss of righting reflex (LORR) assay was used to test Ro15-4513 (20 mg/kg) antagonism of ethanol (3.5 g/kg)-induced hypnosis. An effect of sex was observed on the LORR assay, so males and females were analyzed separately. In male mice, Ro15-4513 markedly reduced ethanol-induced LORR in WT controls, but α4 KO mice were insensitive to this effect of Ro15-4513. In contrast, female KO mice did not differ from WT controls in the antagonistic effects of Ro15-4513 on ethanol-induced LORR. We conclude that Ro15-4513 requires α4-containing receptors for antagonism of ethanol-induced LORR (in males) and motor ataxia.
Highlights
IntroductionThe molecular mechanisms by which alcohol (ethanol) exerts its effects on the brain largely remain an enigma
The molecular mechanisms by which alcohol exerts its effects on the brain largely remain an enigma
The primary goal of this study was to test the hypothesis that α4-containing GABAA-Rs are required in vivo for the mechanism by which the imidazobenzodiazepine Ro15-4513 antagonizes the behavioral signs of ethanol intoxication
Summary
The molecular mechanisms by which alcohol (ethanol) exerts its effects on the brain largely remain an enigma. Understanding the mechanisms of action of this widely used drug is essential for the rational design of therapeutic interventions to combat alcohol use disorders. Γ-Aminobutyric acid (GABA) type A receptors (GABAA-Rs) have long been implicated as key molecular targets of ethanol because drugs that are known to act via GABAA-Rs (i.e., benzodiazepines, barbiturates) produce behavioral effects that are similar to ethanol intoxication (e.g., Hu et al, 1987). Tolerance to these GABAergic agents produces cross tolerance to ethanol (e.g., Khanna et al., 1998). Definitive elucidation of the targets of ethanol and ethanol antagonists has the potential to dramatically impact the search for effective treatments for alcohol abuse and alcoholism
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