The interaction of antidepressant drugs with enteric 5-HT 7 receptors

Abstract

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.

5‐HT7, NEUROGENESIS AND ANTIDEPRESSANTS: A PROMISING THERAPEUTIC AXIS FOR TREATING DEPRESSION

“…55 Interestingly, mianserin, imipramine, amitriptyline and fluoxetine, a pharmacologically diverse range of antidepressants, behave as antagonists at enteric 5-HT 7 receptors. 61 This pharmacological finding corroborates the behavioural data that show 5-HT 7 antagonism producing antidepressant behavioural effects. In contrast, however, citalopram (a highly selective SRI) does not bind to the 5-HT 7 receptor at all.…”

Effects of Some Antidepressant Drugs on Tryptaminergic Responses of the Rat Jejunum

“…Liu/Coupar/Irving The antidepressant drugs previously screened by Lucchelli et al [13] using the guinea-pig ileum 5-HT 7 model displayed similar antagonist profiles in the rat jejunum. Among these drugs, only mianserin produced a surmountable antagonism of 5-CT in the concentration range of 0.1-1 Ìmol/l, giving a pA 2 value of 8.22 B 0.33 (n = 4).…”

“…This was to maintain uniformity with other published data so that results could be compared directly [9,10,13,16,17].…”

“…A series of antidepressant drugs were investigated for potential antagonist activity, since some antidepressants have recently been shown to have affinity for the functional 5-HT 7 receptor of the guinea-pig ileum [13]. We considered it useful to validate the results using a different in vitro preparation, since this finding is of potential clinical relevance to the mechanism of antidepressant action.…”

Centrally acting agents and visceral sensitivity

“…25 It is likely that these properties are related to the reductions in diarrhoea that have been reported in several clinical trials in patients with IBS, [14][15][16] and also to the ability of these drugs to increase gastrointestinal transit time. 26 Interestingly, it has been shown that administration of amitriptyline or fluoxetine to rats for a period of one month using non-psychiatric doses resulted in enhancement of the sensitivity of contractile intestinal muscle serotonin in vitro.…”