Cholera toxin (CT) may induce uncontrolled firing in recurrent networks of secretomotor neurons in the submucous plexus. This hypothesis was tested in chloralose-anaesthetized rats in vivo. The secretory reflex response to graded intestinal distension was measured with, or without, prior exposure to luminal CT. Transmural potential difference (PD) was used as a marker for electrogenic chloride secretion. In controls, distension increased PD and this response was reduced by the neural blocker tetrodotoxin given serosally and the vasoactive intestinal peptide (VIP) receptor antagonist [4Cl-D-Phe⁶,Leu¹⁷]-VIP (2 µgxmin^-1xkg^-1 i.v.), but unaffected by the 5-HT₃ receptor antagonist granisetron, by the nicotinic receptor antagonist hexamethonium, the muscarinic receptor antagonist atropine or by the cyclooxygenase inhibitor indomethacin. Basal PD increased significantly with time in CT-exposed segments, an effect blocked by granisetron, by indomethacin and by [4Cl-D-Phe⁶,Leu¹⁷]-VIP, but not by hexamethonium or atropine. In contrast, once the increased basal PD produced by CT was established, [4Cl-D-Phe⁶,Leu¹⁷]-VIP and indomethacin had no significant effect, while granisetron and hexamethonium markedly depressed basal PD. CT significantly reduced the increase in PD produced by distension, an effect reversed by granisetron, indomethacin and atropine. CT also activated a specific motility response to distension, repeated cluster contractions, but only in animals pretreated with granisetron, indomethacin or atropine. Conclusion: The data are compatible with the hypothesis that CT induces uncontrolled activity in submucous secretory networks. Development of this state depends on 5-HT₃ receptors, VIP receptors and prostaglandin synthesis, while its maintenance depends on 5-HT₃ and nicotinic receptors, but not VIP receptors. CT:s motility effects (probably reflecting myenteric activity) are partially suppressed via a mechanism involving 5-HT₃ and muscarinic receptors and prostaglandin synthesis.