The interaction of antidepressant drugs with enteric 5-HT7 receptors

In this study the functional interaction of the antidepressant drugs amitri ptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative an tidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guineapig ileum. 5-CT induced a concentration-dependent inhibition of the contractile respon se to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory respon se with the following rank affinity order: mianserin > maprotiline greater than or equal to imipramine > amitriptyline. Mianserin was the only antidep ressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 mu M), with an affinity (pA(2)) val ue of 8.1+/-0.6. The antagonism of the other antidepressants was not concen tration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal. 5-CT response (imipramine or maprotiline). The a pparent affinity (pK(B)) 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 c hemical classes behave as antagonists at enteric 5-HT7 receptors through co mpetitive or allosteric mechanisms. This evidence extends our previous find ings demonstrating the interaction of antidepressants with other 5-HT recep tors, namely 5-HT3 and 5-HT4 receptors.