4-hydroxymethylphenidate and Stomach-Ulcer

The dopamine agonists and promoters bromocriptine, bupropion, and p-hydroxymethylphenidate (a peripherally acting methylphenidate analog) reduced basal gastric acid secretion in rats, while the dopamine antagonists haloperidol, pimozide and metoclopramide augmented gastric acid output. Stress ulcer formation and plasma corticosterone levels were markedly reduced by l-dopa given either intraperitoneally or intracerebroventricularly as well as by intraperitoneally administered p-hydroxymethylphenidate. Domperidone, a peripheral dopamine receptor blocker, produced variable effects on stress responses, indicating a wider spectrum of action than hitherto realized for this compound. The results strongly support a role for both central and peripheral dopaminergic activity in reducing the pathological consequences of exposure to stress.

Topics: Animals; Corticosterone; Domperidone; Dopamine; Dopamine Antagonists; Gastric Juice; Immobilization; Levodopa; Methylphenidate; Metoclopramide; Rats; Stomach Ulcer; Stress, Psychological

Dopamine (DA) and DA agonists have been shown to exert a protective role against the formation of duodenal ulcers. The effect of stimulation of DA receptors on the development of stress-induced gastric ulcers is currently unknown. Accordingly, we evaluated the effect of several DA agonists on the development of gastric ulcers induced by 3 h of cold + restraint stress (CRS) in rats. Apomorphine, d-amphetamine, methylphenidate, and threo-dl-p-hydroxymethylphenidate (an hydroxylated analog of methylphenidate), significantly reduced both the incidence and severity of CRS-induced gastric ulcers. The gastric cytoprotection afforded by these agents was dose-related, and completely antagonized by pretreatment with the peripherally acting DA antagonist domperidone. Because domperidone blocks peripheral, but not central, DA receptors, and since the entry of threo-dl-p-hydroxymethylphenidate across the blood-brain barrier into the brain is restricted to a great extent, we conclude that stimulation of peripheral DA receptors is primarily involved in the gastric cytoprotection induced by dopamimetics.

Topics: Animals; Apomorphine; Dextroamphetamine; Domperidone; Dopamine; Male; Methylphenidate; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological