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α2-adrenoceptors are known to mediate gastroprotective effect in both acid-dependent and acid-independent ulcer models. The aim of the present study was to determine, which of the three α2-adrenoceptor subtypes (α2A, α2B or α2C) is responsible for this protection. Various α2-adrenoceptor agonists and antagonists were administered intracerebroventricularly (i.c.v.) to C57BL/6 mice with deletion of genes encoding the different subtypes. The gastric mucosal damage was induced by orally injected acidified ethanol. Both the non-selective α2-adrenoceptor agonist clonidine (0.3–2.8 nmol) and the α2B/C-adrenoceptor subtype preferring agonist ST-91 (0.5–11.5 nmol) induced dose-dependent gastroprotective effect in wild type, α2A-, α2B- and α2C-KO mice. In contrast, the α2A-adrenoceptor subtype agonist oxymetazoline (0.07–84 nmol i.c.v.) reduced only slightly the development of ethanol-induced ulcers. The effect of clonidine was antagonized by the non-selective antagonist yohimbine (25 nmol) and the α2B/C-adrenoceptor antagonist ARC 239 (10.4 nmol), but not by the α2A-adrenoceptor antagonist BRL 44408 (7.5 nmol). ARC 239 also reversed the effect of clonidine in α2A-, α2B- and α2C-KO mice, while the selective α2C-adrenoceptor antagonist JP 1302 (52 nmol) antagonized that only in α2B-KO, but not in α2A- and α2C-KO mice. These results suggest that α2B- and α2C-adrenoceptor subtypes can equally contribute to the mediation of gastroprotective effect induced by α2-adrenoceptor agonists in mice.