Drugs acting at central benzodiazepine receptors attenuate ethanol-induced gastric lesions in rats

Abstract

The characteristics of the receptors involved in the protective action of benzodiazepines against ethanol-induced gastric lesions were investigated by studying the effect of benzodiazepine ligands on such lesions in both intact and unilaterally vagotomized rats. Clonazepam [5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H-1,4-benzodiazepine-2-one] a specific central-type receptor agonist (0.625–2.5 mg/kg p.o. or i.p.) and CGS 9896 [2-(4-chlorophenyl)-2,5-dihydropyrazolo{4,3-c}quinoline-3(3 H)-one] a non-sedative partial agonist with anxiolytic properties (2.5–10 mg/kg p.o.) significantly reduced the gastric damage induced by ethanol (10 ml/kg of a 50% solution v/v p.o.) in non-vagotomized rats but Ro 5-4864 [7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2 H-1,4-benzodiazepine-2-one] a pure peripheral-type receptor agonist (5–20 mg/kg p.o.) failed to affect this damage. The protective action of clonazepam and CGS 9896 against ethanol-induced gastric lesions was blocked, dose dependently, by the central-type receptor antagonist, flumazenil [ethyl8-fluoro-5,6-5-methyl-6-oxo-4 H-imidazo{1,4}benzodiazepine-3-carboxylate] (1.25–20 mg/kg i.p.). In the unilaterally vagotomized rat, ethanol produced lesions in the right (vagotomized) and the left (non-vagotomized) halves of the gastric mucosa to nearly the same extent, while clonazepam and CGS 9896 uniformly decreased the lesions in both halves. It is concluded that central-type benzodiazepine receptors located in the stomach, specifically those mediating the anxiolytic effect of benzodiazepines, are involved in the protective action of benzodiazepines against ethanol-induced gastric lesions.