Neural 5-hydroxytryptamine receptors regulate chloride secretion in guinea pig distal colon

The effects of 5-hydroxytryptamine (5-HT) on epithelial short-circuit current (Isc) were determined and related to the 5-HT effects on electrical and synaptic behavior of neurons in the submucosal plexus of the guinea pig colon. 5-HT evoked a biphasic increase in Isc that was reduced by bumetanide, Cl(-)-free solutions, atropine, and mecamylamine and abolished by tetrodotoxin. The 5-HT response was mimicked by 2-methyl-5-HT, but not by 5-hydroxyindalpine, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, and 5-methoxytryptamine (5-MeOT). ICS 205-930 suppressed the 5-HT response. Electrical field stimulation of submucosal neurons evoked an increase in Isc indicative of Cl- secretion that was reduced by 5-MeOT and enhanced by 2-methyl-5-HT. Application of 5-HT to submucosal neurons by micropressure ejection resulted in membrane depolarization, augmented excitability, and repetitive spike discharge. The depolarization was biphasic, consisting of rapidly and slowly activating components. The rapidly activating component was suppressed by ICS 205-930. Fast excitatory postsynaptic potentials evoked by electrical stimulation of interganglionic connectives were suppressed by 5-HT and 5-MeOT. These results suggest that 5-HT activates 5-HT3 receptors, which mediate fast excitatory responses in submucosal neurons, leading to release of acetylcholine at nicotinic and muscarinic synapses and stimulation of Cl- secretion. Presynaptic inhibition suppresses acetylcholine release and results in attenuation of neurally evoked Cl- secretion.