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Evidence for the involvement of 5-hydroxytryptamine 4 receptors in 5-hydroxytryptophan-induced diarrhea in mice.

Abstract
The objective of this study was to characterize the receptor(s) to 5-HT mediating 5-HTP-induced diarrhea in mice. The severity of diarrhea in mice was assessed using an arbitary scoring scale ranging from 0 (normal stools) to 3 (watery diarrhea). Administration of 5-HTP (1-30 mg/kg i.p.) produced a dose-dependent increase in diarrhea score (ED50, 1.47 mg/kg i.p.). 5-HTP (10 mg/kg i.p.)-induced diarrhea was unaffected by atropine (3 mg/kg i.p.) but was completely abolished by the aromatic L-amino acid decarboxylase inhibitor benserazide (10 mg/kg i.p.). Pretreatment (5 min before 5-HTP) with DAU 6285, a marginally selective 5-HT4 receptor antagonist, significantly inhibited 5-HTP-induced diarrhea (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, significantly 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 E2 (30 micrograms/kg i.p.)-induced diarrhea in mice. DAU 6285 significantly inhibited 16,16-dimethyl prostaglandin E2-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.(ABSTRACT TRUNCATED AT 250 WORDS)
AuthorsS S Hedge, T M Moy, M R Perry, M Loeb, R M Eglen
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 271 Issue 2 Pg. 741-7 (Nov 1994) ISSN: 0022-3565 [Print] United States
PMID7965791 (Publication Type: Journal Article)
Chemical References
  • Benzimidazoles
  • Bridged Bicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Dioxanes
  • Indoles
  • Piperidines
  • Receptors, Serotonin
  • Sulfonamides
  • DAU 6285
  • SB 204070A
  • Benserazide
  • Atropine
  • 5-Hydroxytryptophan
  • GR 113808
Topics
  • 5-Hydroxytryptophan (pharmacology)
  • Animals
  • Atropine (pharmacology)
  • Benserazide (pharmacology)
  • Benzimidazoles (pharmacology)
  • Bridged Bicyclo Compounds (pharmacology)
  • Bridged Bicyclo Compounds, Heterocyclic
  • Diarrhea (chemically induced)
  • Dioxanes (pharmacology)
  • Indoles (pharmacology)
  • Male
  • Mice
  • Parasympathetic Nervous System (physiology)
  • Piperidines (pharmacology)
  • Receptors, Serotonin (drug effects, physiology)
  • Sulfonamides (pharmacology)

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