Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors

Nearly 30% of patients treated with metformin experience gastrointestinal s ide effects. Since release of 5-hydroxytryptamine (5-HT) from the intestine is associated with nausea, vomiting, and diarrhea, we examined whether met formin induces 5-HT release from the intestinal mucosa. In 40% of tissue bi opsy specimens of human duodenal mucosa, metformin (1, 10, and 30 mu M) cau sed an increase in 5-HT outflow by 35, 70, and 98%, respectively. Peak incr eases in 5-HT outflow were observed after 10-15 min exposure to metformin, returning to baseline levels after 25 min. Tetrodotoxin(1 mu M) reduced by about 50% the metformin-evoked increase in 5-HT outflow (P<0.05). Metformin -evoked release was not affected by scopolamine + hexamethonium, propranolo l, the 5-HT3 receptor antagonist dolasetron, naloxone, or the NK1 receptor antagonist L703606. In the presence of tetrodotoxin (1 mu M), somatostatin (1 mu M) further reduced metformin-induced 5-HT release by 15-20%. In view of the 5-HT releasing effects of selective 5-HT3 receptor agonists to which metformin (N-N-dimethyl-biguanide) is structurally related, we inv estigated whether metformin directly interacts with 5-HT3 receptors. Recept or binding (inhibition of [H-3]-GR65630 binding) and agonist effects (stimu lation of [C-14]-guanidinium influx) at 5-HT3 receptors were studied in mur ine neuroblastoma N1E-115 cells, which express functional 5-HT3 receptors. Metformin up to 0.3 mM failed to inhibit [H-3]-GR65630 binding and to modif y displacement of [H-3]-GR65630 binding induced by 5-HT. 5-HT (3 mu M) stim ulated the influx of [C-14]-guanidinium in intact N1E-115 cells. Metformin up to 1 mM failed to modify basal influx, 5-HT-induced influx, and 5-HT+ su bstance P-induced influx of [C-14]-guanidinium. Our results indicate that m etformin induces 5-HT3 receptor-independent release of 5-HT from human duod enal mucosa via neuronal and non-neuronal mechanisms. Part of the gastroint estinal side effects observed during treatment with metformin could, thus, be produced by the release of 5-HT and other neurotransmitter substances wi thin the duodenal mucosa.