EVIDENCE FOR THE INVOLVEMENT OF 5-HYDROXYTRYPTAMINE-4 RECEPTORS IN HYDROXYTRYPTOPHAN-INDUCED DIARRHEA IN MICE

The objective of this study was to characterize the receptor(s) to 5-H T mediating 5-HTP-induced diarrhea in mice. The severity of diarrhea i n mice was assessed using an arbitary scoring scale ranging from 0 (no rmal stools) to 3 (watery diarrhea). Administration of 5-HTP (1-30 mg/ kg i.p.) produced a dose-dependent increase in diarrhea score (ED(50), 1.47 mg/kg i.p.). 5-HTP (10 mg/kg i.p.)-induced diarrhea was unaffect ed by atropine (3 mg/kg i.p.) but was completely abolished by the arom atic L-amino acid decarboxylase inhibitor benserazide (10 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with DAU 6285, a marginally selecti ve 5-HT4 receptor antagonist, significantly inhibited 5-HTP-induced di arrhea (ID50, 0.58 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with GR 113808 or SB 204070, two highly selective 5-HT4 antagonists, signi ficantly inhibited 5-HTP-induced diarrhea with ID50 estimates of 0.31 and 0.003 mg/kg i.p., respectively. The maximal inhibition produced by DAU 6285, GR 113808 and SB 204070 was 63%, 68% and 36%, respectively. Neither GR 113808 (1 and 3 mg/kg i.p.) nor SB 204070 (0.1 and 1 mg/kg i.p,) had any effect on 16,16-dimethyl prostaglandin E(2) (30 mu g/kg i.p.)-induced diarrhea in mice. DAU 6285 significantly inhibited 16,1 6-dimethyl prostaglandin E(2)-induced diarrhea at the highest dose (3 mg/kg i.p.). Pretreatment (30 min before 5-HTP) with methysergide (0.1 -3 mg/kg i.p.), metergoline (0.01-0.1 mg/kg i.p.), ketanserin (0.01-1 mg/kg i.p.), YM 060 (0.01-0.1 mg/kg i.p.) or ondansetron (0.01-3 mg/kg i.p.) had no significant effects on 5-HTP-induced diarrhea. Granisetr on significantly inhibited 5-HTP-induced diarrhea only at high (nonspe cific) doses (0.3 and 3 mg/kg i.p.). These data suggest that 5-HTP-ind uced diarrhea is mediated by 5-HT operating via a noncholinergic mecha nism and involves, at least in part, the activation of 5-HT4 receptors .