Document Detail

The interaction of antidepressant drugs with central and peripheral (enteric) 5-HT3 and 5-HT4 receptors.
MedLine Citation:
PMID:  7780635     Owner:  NLM     Status:  MEDLINE    
1. 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. 2. 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 microM. Litoxetine had an IC50 of 0.3 microM. 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 > or = 20 microM). 3. 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). 4. Fluoxetine (0.1-1 microM) and litoxetine (0.3-3 microM) 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 microM), 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 microM) was ineffective on the high-potency phase, but caused a rightward shift of the low-potency phase (pKB: 6.1 +/- 0.01). 5. Responses to 2-methyl-5-HT were inhibited by 1 microM fluoxetine (pKB: 5.4 +/- 0.02). Like clomipramine(30 and 100 nM), litoxetine (1 and 3 microM) produced rightward displacements of 2-methyl-5-HT-induced contractions, which were virtually independent of antidepressant concentration (pKB values: 6.0 +/- 0.02 and 5.5 +/- 0.01, respectively). At higher concentrations, fluoxetine (3 microM) and clomipramine (300 nM)markedly reduced the 2-methyl-5-HT response maximum. Paroxetine (1 micro M) was ineffective.6. Responses to 5-MeOT were shifted to the right by fluoxetine (0.1-1 micro M) and litoxetine (1 and 3 microM)in a concentration-dependent manner. At higher concentrations, fluoxetine (3 microM) markedly reduced the 5-MeOT response maximum, an effect also observed with 100 and 300 nM clomipramine. Paroxetine(1 microM) was ineffective.7. 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.8. 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 allostericant agonism 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.
A Lucchelli; M G Santagostino-Barbone; A Barbieri; S M Candura; M Tonini
Related Documents :
1988665 - Serotonergic modulation of the release of endogenous norepinephrine from rat hypothalam...
25352885 - B1 but not b2 bradykinin receptor agonists promote du145 prostate cancer cell prolifera...
8298805 - Blockade of human atrial 5-ht4 receptors by gr 113808.
2322835 - 5-ht3 receptors modulate spinal nociceptive reflexes.
16384835 - Effects of chronic cold exposure on the endothelin system.
23423265 - Taste perception: from the tongue to the testis.
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  114     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  1995 Mar 
Date Detail:
Created Date:  1995-07-14     Completed Date:  1995-07-14     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1017-25     Citation Subset:  IM    
Institute of Pharmacology, School of Pharmacy, University of Pavia, Italy.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Antidepressive Agents, Second-Generation / pharmacology*
Binding, Competitive / drug effects
Brain Neoplasms / metabolism
Central Nervous System / drug effects*
Corpus Striatum / drug effects,  metabolism
Electric Stimulation
Guinea Pigs
Ileum / drug effects
Muscle, Smooth, Vascular / drug effects,  physiology
Myenteric Plexus / drug effects,  physiology
Neuroblastoma / metabolism
Peripheral Nervous System / drug effects*
Receptors, Serotonin / drug effects*
Serotonin Antagonists / pharmacology
Serotonin Uptake Inhibitors / pharmacology*
Tumor Cells, Cultured
Reg. No./Substance:
0/Antidepressive Agents, Second-Generation; 0/Receptors, Serotonin; 0/Serotonin Antagonists; 0/Serotonin Uptake Inhibitors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Sensitization by calyculin A of brain capillary endothelial cells to endothelin-1.
Next Document:  Pharmacological characterization of alpha 1-adrenoceptor subtypes in rat heart: a binding study.