The occurrence and characteristics of binding sites specific for gamma-aminobutyric acid (GABA) and muscimol in the rat stomach were examined by biochemical and autoradiographic techniques, and the effects of GABAergic model compounds on gastric ulceration induced by chemical irritation was studied in intact and unilaterally vagotomized rats. Specific binding sites for [3H]GABA and [3H]muscimol, which showed the characteristics of GABAA receptors, were demonstrated on gastric membranes. Specific muscimol binding sites were found in all regions of the stomach and were present in both the mucosal layer and the remaining tissue of the stomach. Oral pretreatment of the rats with GABA, selective GABAA receptor agonists, or inhibitors of GABA degradation protected the gastric mucosa against the ulcers induced by acidified ethanol (chemical irritant), in both intact and vagotomized rats. These findings are consistent with the view that a subpopulation of GABAA receptors in the rat stomach may mediate the anti-ulcer effect.