5-HT4 receptors contribute to the motor stimulating effect of levosulpiride in the guinea-pig gastrointestinal tract.

Abstract Background. The dopamine D 2 receptor antagonist levosulpiride is a substituted benzamide derivative, whose gastrokinetic properties are exploited clinically for the management of functional dyspepsia. However, for other benzamide derivatives, such as cisapride and mosapride, agonism towards serotonin 5-HT 4 receptors is considered the main mechanism leading to gastrointestinal prokinesia. Aims. To assess whether levosulpiride is able to activate 5-HT 4 receptors in the guinea-pig isolated gastrointestinal tract. Materials and methods. Circular muscle strips from gastric antrum, and colonic longitudinal muscle strips were used to detect electrically stimulated neurogenic contractions. The effect of levosulpiride was assessed in the absence and presence of GR125487, a selective 5-HT 4 receptor antagonist. Furthermore, potential interaction of levosulpiride with 5-HT 3 receptors and tissue cholinesterases was assessed in unstimulated ileal longitudinal muscle-myenteric plexus preparations. Results. Antral and colonic strip contractions were cholinergic/tachykinergic in nature. Micromolar concentrations of levosulpiride potentiated submaximal responses, through a mechanism competitively antagonized by GR125487 (p K B =9.4). In LMMPs, levosulpiride slightly affected contractions caused by the 5-HT 3 receptor agonist 2-methyl-5-HT, and had no effect on contractions to exogenous acetylcholine. Conclusions. Our results indicate that levosulpiride acts as a moderate agonist at the 5-HT 4 receptor. This property, together with antagonism at D 2 receptors, may contribute to its gastrointestinal prokinetic effect.