Clozapine, a dopamine DA4 receptor antagonist, reduces gastric acid secretion and stress-induced gastric mucosal injury.
Dopamine and its agonists modulate a variety of gastrointestinal functions. In light of the increasing attention directed toward novel dopamine receptors and compounds that are active at these sites, we examined the effects of a dopamine D4 antagonist and putative antipsychotic, clozapine, in a model of conscious basal gastric acid secretion and in a model of stress-induced gastric mucosal injury. At a dose of 10.0 mg/kg i.p., clozapine significantly inhibited basal gastric acid secretion by 84% relative to vehicle. Lower doses (2.5 and 5.0 mg/kg) were inactive. Doses of 2.5, 5.0 and 7.5 mg/kg i.p. all significantly reduced restraint stress-induced gastric mucosal injury in rats. The highest dose inhibited gastric lesions by 70% relative to vehicle. We conclude that dopamine D4 receptors, present in high concentrations in mesolimbic brain regions, modulate gastric function and pathology in addition to mesolimbic D1 receptors, whose role in gastrointestinal function is already established.
Glavin
G B
GB
Department of Pharmacology, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Hall
A M
AM
D000818:Animals; D003024:Clozapine / Q000494:pharmacology*; D018492:Dopamine Antagonists; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D013272:Stomach Diseases / Q000209:etiology / Q000517:prevention & control*; D013312:Stress, Physiological / Q000150:complications*
D018492:Dopamine Antagonists; C493601:Drd4 protein, rat; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D003024:Clozapine