5-Hydroxytryptamine-Mediated Responses in Myenteric Neurons of the Guinea Pig Gastric Corpus: Effect of ICS 205-930 and Cisapride

Abstract

The effects of serotonin (5-hydroxytryptamine, or 5-HT) on the neurophysiologic behavior of guinea pig gastric myenteric neurons were investigated in vitro using conventional intracellular recording methods. The predominant effect consisted of a brief, rapidly desensitizing depolarization in 48 of 78 neurons. During the depolarization the membrane resistance decreased and the excitability of the neurons increased, as indicated by action potential discharge during previously subthreshold depolarizing current pulses. The fast response to 5-HT was mimicked by the 5-HT3 receptor agonist 2-methyl-5-HT. Both cisapride and the selective 5-HT3 receptor antagonist ICS 205–930 dose-dependently reduced the fast 5-HT and 2-methyl-5-HT response. 5-HT evoked in 3 of 78 neurons a long-lasting depolarization in addition to the initial fast response. This response was accompanied by an increased excitability level of the cell. The long-lasting response was blocked by the 5-HT1p receptor antagonist N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5-HTP-DP) and mimicked by the 5-HT1p receptor agonist 5-hydroxyindalpine (5-OHIP). In most neurons 5-HT had no effect on the cholinergic fast excitatory postsynaptic potentials (fEPSPs) evoked by electrical stimulation of interganglionic fiber tracts. Occasionally, it reduced the fEPSP amplitude. In another subset of neurons it increased the fEPSP amplitude. As a result, the fEPSP reached threshold for spike discharge. The results indicate that the primary effect of 5-HT on myenteric neurons is mediated through 5-HT3 receptors whereas only a minor proportion of the neurons exhibited 5-HT1p-mediated responses. ICS 205–930 and cisapride act as 5-HT3 receptor antagonists in gastric myenteric neurons.