The interaction of antidepressant drugs with central and peripheral (enteric) 5-HT3 and 5-HT4 receptors

A. Lucchelli, M. G. Santagostino-Barbone, A. Barbieri, S. M. Candura, M. Tonini

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A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea-pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5-HT3 and 5-HT4 receptors. Clomipramine, paroxetine and fluoxetine inhibited [3H]-DAU 6215 binding to 5-HT3 recognition sites in NG 108-15 cells with IC50 values in the range 1.3-4 μM. Litoxetine had an IC50 of 0.3 μM. The specific binding of [3H]-GR 113808 to 5-HT4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC50 values ≥ 20 μM). In whole ileal segments, concentration-response curves to 5-HT were biphasic, with the high- and low-potency phases involving 5-HT4 and 5-HT3 receptors, respectively. Curves to 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: a 5-HT3 receptor agonist) and 5-methoxytryptamine (5-MeOT: a 5-HT4 receptor agonist) were monophasic. All antidepressants were used at concentrations lacking anticholinoceptor properties, as demonstrated in both electrically stimulated longitudinal muscle-myenteric plexus preparations (LMMPs) and in unstimulated LMMPs following addition of acetylcholine (100 nM). Fluoxetine (0.1-1 μM) and litoxetine (0.3-3 μM) antagonized both the high- and low-potency phases of the 5-HT curve. Schild analysis for the low-potency phase yielded pA2 estimates of 6.6 ± 0.3 (Schild slope of 1.1) and of 6.6 ± 0.1 (Schild slope of 1.1), respectively. At higher concentrations (3 μM), fluoxetine markedly inhibited the 5-HT response maximum. Clomipramine (10-300 nM) inhibited, by a mechanism independent of concentration, both phases of the 5-HT curve with a reduction of the maximum response. Paroxetine (1 μM) was ineffective on the high-potency phase, but caused a rightward shift of the low-potency phase (pK(B): 6.1 ± 0.01). Responses to 2-methyl-5-HT were inhibited by 1 μM fluoxetine (pK(B): 5.4 ± 0.02). Like clomipramine (30 and 100 nM), litoxetine (1 and 3 μM) produced rightward displacements of 2-methyl-5-HT-induced contractions, which were virtually independent of antidepressant concentration (pK(B) values: 6.0 ± 0.02 and 5.5 ± 0.01, respectively). At higher concentrations, fluoxetine (3 μM) and clomipramine (300 nM) markedly reduced the 2-methyl-5-HT response maximum. Paroxetine (1 μM) was ineffective. Responses to 5-MeOT were shifted to the right by fluoxetine (0.1-1 μM) and litoxetine (1 and 3 μM) in a concentration-dependent manner. At higher concentrations, fluoxetine (3 μM) markedly reduced the 5-MeOT response maximum, an effect also observed with 100 and 300 nM clomipramine. Paroxetine (1 μM) was ineffective. In unstimulated LMMPs, the excitatory effects evoked by 5-HT, 2-methyl-5-HT and 5-MeOT and the antagonism produced by 300 nM clomipramine were comparable to those obtained in whole ileal segments. This suggests that 5-HT contained in the mucosa of whole preparations does not interfere with agonist-induced contractile responses and with the inhibitory effect of antidepressant drugs. In conclusion, our results show that clomipramine, fluoxetine, paroxetine and litoxetine possess low to moderate potency/affinity at both central and peripheral (enteric) 5-HT3 receptors. In contrast, all four antidepressants are virtually ineffective at central 5-HT4 receptors. Inhibition of 5-HT4 receptor-mediated ileal contractions by fluoxetine, litoxetine and clomipramine may result from allosteric antagonism or, more likely, from post-receptor blockade of second messenger generation. The interaction of antidepressants with central and peripheral 5-HT3 and 5-HT4 receptors may be relevant for both potential therapeutic action and adverse effects at gastrointestinal level.

Original languageEnglish
Pages (from-to)1017-1025
Number of pages9
JournalBritish Journal of Pharmacology
Issue number5
Publication statusPublished - 1995


  • 5-HT receptors
  • 5-HT receptors
  • Antidepressant drugs (clomipramine, fluoxetine, paroxetine, litoxetine)
  • Guinea-pig ileum
  • NG 108-15 cells
  • Pig corpus striatum

ASJC Scopus subject areas

  • Pharmacology

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