Ss. Hegde et al., EVIDENCE FOR THE INVOLVEMENT OF 5-HYDROXYTRYPTAMINE-4 RECEPTORS IN HYDROXYTRYPTOPHAN-INDUCED DIARRHEA IN MICE, The Journal of pharmacology and experimental therapeutics, 271(2), 1994, pp. 741-747
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
.