CENTRAL-NERVOUS-SYSTEM AND GUT INTERACTIONS - DOPAMINE AND EXPERIMENTAL GASTRODUODENAL LESIONS

There is increasing evidence for brain regulation of gastroduodenal fu nction and pathological responses. This laboratory has demonstrated a significant role for dopamine (DA) as a modulator of gastrointestinal function and disease. Using models of both acute (ethanol restraint st ress; cysteamine) and chronic (iodoacetamide-induced gastritis) gastro duodenal mucosal injury, as well as tests of gastric secretory functio n (conscious basal gastric acid secretion; pylorus ligation; ex: vivo gastric chamber), we have shown that DA, particularly DA(1)/D-1 recept or agonists are powerful gastroprotective agents. This action is demon strable upon peripheral administration as well as central (particularl y intramesolimbic) administration. DA(1)/D-1 agonists such as SKF38393 and SKF75670C reduce experimental gastric mucosal injury and secretio n while antagonists of these receptors, including SCH23390, worsen exp erimental gastroduodenal lesions and augment secretion. That there exi sts a significant central component to DA-induced gastroprotection is demonstrated by data showing that rats assessed as anxiety prone, deve lop a greater degree of experimentally induced gastric damage, require greater amounts of DA agonists for 50% gastroprotection and respond t o exogenous stress challenge with greater central DA turnover and loss , relative to rats assessed as low in anxiety. Very recently, we showe d chat dopamine D-4 receptor blockade by clozapine and activation of d opamine D-3 receptors by 7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7 -OHDPAT) are also associated with antisecretory and gastroprotective e ffects. Taken together, these data suggest that: (i) DA is a significa nt component of endogenous gastroprotection; (ii) central DA, particul arly mesolimbic DA, is an important determinant of peripheral gastrodu odenal responses to exogenous chemical and stress challenges; and (iii ) the hypothesis that several DA receptor subtypes modulate gastroduod enal function and pathology is increasingly plausible.