The mechanism for the gastric antisecretory action of desmethylimipramine (DMI) was studied using the pylorus-ligated rat preparation. DMI was approximately 40 times more potent in decreasing gastric acid secretion when given into the lateral ventricles of the brain than when administered intravenously. The antisecretory effects of DMI could be blocked by the alpha 2-adrenoceptor antagonists yohimbine and SK&F 72223 and mimicked by central administration of an alpha 2-agonist. It could not be blocked by the alpha 1-antagonist prazosin or mimicked by alpha 1-adrenoceptor agonists. SK&F 72223 and yohimbine themselves produced small increases in gastric acid, but the increase output by SK&F 72223 failed to reduce the antisecretory response to atropine. Since DMI is not an alpha 2-adrenoceptor agonist, but is a potent inhibitor of norepinephrine uptake, these data suggest that the effects of DMI on gastric acid secretion are mediated indirectly via inhibition of catecholamine uptake at central synapses containing alpha 2-adrenoceptors.