CLOZAPINE, A DOPAMINE DA(4) RECEPTOR ANTAGONIST, REDUCES GASTRIC-ACIDSECRETION AND STRESS-INDUCED GASTRIC-MUCOSAL INJURY

Dopamine and its agonists modulate a variety of gastrointestinal funct ions. In light of the increasing attention directed toward novel dopam ine receptors and compounds that are active at these sites, we examine d the effects of a dopamine D-4 antagonist and putative antipsychotic, clozapine, in a model of conscious basal gastric acid secretion and i n a model of stress-induced gastric mucosal injury. At a dose of 10.0 mg/kg i.p., clozapine significantly inhibited basal gastric acid secre tion 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 reduc ed restraint stress-induced gastric mucosal injury in rats. The highes t dose inhibited gastric lesions by 70% relative to vehicle. We conclu de that dopamine D-4 receptors, present in high concentrations in meso limbic brain regions, modulate gastric function and pathology in addit ion to mesolimbic D-1 receptors, whose role in gastrointestinal functi on is already established.