Intestinal motilin is known to stimulate gastrointestinal motility. Recently, it was shown that the motilin gene and the motilin receptor are expressed in various regions of the brain. We studied whether motilin can activate pathways in the rat hippocampus to stimulate gastric motility. Gastric motility was monitored in conscious rats, whereas extracellular electrical activity recordings of the hippocampus were performed on anaesthetized rats to measure the influence of microinjection of motilin and CCK-8 into the hippocampus and into the cerebral ventricles. We found that neurons in the CA3 region of the hippocampus are sensitive to gastric distension, and that injection of motilin into the hippocampus increased the amplitude of gastric contractions by 35.3+/-6.8%, while CCK-8 injection inhibited motility by -27.3+/-6.8%. The hippocampal motilin-induced stimulation of gastric motility (30.6+/-5.5%) was completely abolished by subdiaphragmal vagotomy (-2.8+/-4.4%) but unaffected by the intravenously applied receptor blockers atropine, phentolamine and propranolol. In vivo extracellular recordings of gastric distension-responsive CA3 neurons revealed that intracerebroventricular administration of motilin increased firing while CCK-8 inhibited firing. These opposite effects of motilin and CCK-8 fit with the nature of the actions of these gut-brain peptides on gastric motility. Our findings suggest that the stimulation of gastric motility by motilin administered in the hippocampus reflects the existence of a functional interaction between the hippocampus and a vago-vagus reflex running via a noncholinergic and nonadrenergic efferent pathway.