The selectivity and specificity of fenmetozole (DH-524) [2(3,4-dichlorophenoxy-methy))2-imidazole HCl] as an antagonist of the actions of ethanol were examined. Fenmetozole (15-30 g/kg) reduced ethanol-induced impairment of the aerial righting reflex without changing blood or brain ethanol content, indicating that the antagonistic actions of fenmetozole were not due to change in the pharmacokinetics of ethanol. Since fenmetozole also reduced aerial righting reflex impairment due to phenobarbital, chlordiazepoxide, and halothane, this action of fenmetozole was not specific to ethanol. In mice, both the ethanolinduced increase in locomotor activity at 2.0 g/kg and the decrease caused by 4.0 g/kg were antagonized by fenmetozole. In addition, fenmetozole attenuated the ethanol-induced reduction in cerebellar cyclic guanosine monophosphate (cGMP) content, but the drug also significantly elevated cGMP levels in this tissue when given alone. Fenmetozole did not alter ethanolinduced increases in punished drinking in a conflict test, except at a high dose which alone decreased both punished and unpunished responding. Fenmetozole also failed to precipitate ethanol withdrawal-like reactions when given to physically-dependent, intoxicated rats. Thus, the antagonistic action of fenmetozole against ethanol would not seem to be related to a specific receptor interaction but rather may be the result of a physiological antagonism.
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