Stimulation of gastric acid secretion by progesterone metabolites as neuroactive steroids in anesthetized rats

The effect of neuroactive progesterone metabolites, 5 alpha- and 5 beta-pre gnan-3 alpha-ol-20-one, and their stereoisomers at the 3 C site, 5 alpha- a nd 5 beta-pregnan-3 beta-ol-20-one, on gastric acid secretion was investiga ted in urethane-anesthetized rats. Both 5 alpha- and 5 beta-pregnan-3 alpha -ol-20-one dose-dependently (0.3-3 mg.kg(-1), i.v.) stimulated gastric acid secretion with an early onset of action. Their potency and efficacy were a lmost the equivalent of one another. In contrast, their stereoisomers did n ot have asignificant effect even at 10 mg.kg(-1) (i.v.). The 5 beta-pregnan -3 alpha-ol-20-one (3 mg.kg(-1), i.v.)-stimulated gastric acid secretion wa s remarkably inhibited by bilateral vagotomy or pretreatment with atropine (1 mg.kg(-1), i.v.). An antagonist of the GABA(A) receptor, picrotoxin, at 3 and 6 mg.kg(-1) (i.v,), significantly inhibited the 5 beta-pregnan-3 alph a-ol-20-one (3 mg.kg(-1), i.v.)-stimulated gastric acid secretion. These re sults indicate that naturally occurring neuroactive steroids, 5 alpha- and 5 beta-pregnan-3 alpha-ol-20-one, stimulate gastric acid secretion in a ste reoselective and dose-dependent manner in urethane-anesthetized rats. It is likely that the action of these neuroactive steroids is of central origin and that interaction with GABA(A) receptors and stimulation of vagal pathwa y are involved in its mechanism of action. (C) 2000 Elsevier Science Ltd. P ublished by Editions scientifiques et medicales Elsevier SAS.