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

Abstract

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. 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 musclemyenteric plexus preparations (LMMPs) and in unstimulated LMMPs following addition of acetylcholine (100 nM). 4 Fluoxetine (0.1-1 JM) and litoxetine (0.3-3JM) 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 JM), 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 JM) 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 JAM fluoxetine (pKB: 5.4 ± 0.02). Like clomipramine (30 and 100 nM), litoxetine (1 and 3 JAM) 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 JM) and clomipramine (300 nM) markedly reduced the 2-methyl-5-HT response maximum. Paroxetine (1 JAM) was ineffective.6 Responses to 5-MeOT were shifted to the right by fluoxetine (0.1-1 JAM) and litoxetine (1 and 3fJM) in a concentration-dependent manner. At higher concentrations, fluoxetine (3 JlM) markedly reduced the 5-MeOT response maximum, an effect also observed with 100 and 300 nM clomipramine. Paroxetine (1 JM) 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.

Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac)

“…Fluoxetine blocks different types of nAcChoRs with different strengths, and these effects show some similarities with the action of fluoxetine on 5HT 3 receptors (25)(26)(27). Thus, fluoxetine inhibits the membrane currents elicited by activation of both muscle (␣ 1 ␤ 1 ␥␦) and neuronal (␣ 2 ␤ 4 or ␣ 3 ␤ 4 ) nAcChoRs, either by increasing the rate of receptor desensitization and͞or by inducing channel blockage, which may indirectly facilitate the desensitizing state of the receptor.…”

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

“…Using the NIMH Psychoactive Drug Screening Program database, we did not find any study looking at the binding affinity of fluoxetine at the mouse 5-HT 4 receptor. The only study looking at binding affinities of fluoxetine for serotoninergic receptor demonstrated negligible binding of fluoxetine to the 5-HT 4 receptor in pig striatal membranes (Lucchelli et al, 1995). In addition, quantitative autoradiography revealed that the binding of the 5-HT 4 receptor ligand [ 3 H]GR113808 was not significantly changed in fluoxetine-treated mice (Kobayashi et al, 2012).…”

Blockage of 5HT2Cserotonin receptors by fluoxetine (Prozac)

“…It is generally believed that fluoxetine exerts its therapeutic effects by enhancing serotonergic transmission, exclusively through inhibition of serotonin (5-hydroxytryptamine; 5HT) transporters with minimal or no effects on other neurotransmitter receptors (1,2). However, it has been shown that fluoxetine inhibits 5HT binding in the choroid plexus (3), that it appears to be an agonist of 5HT 2C receptors in cultured astrocytes (4), and that it inhibits currents mediated by 5HT 3 receptors in rat nodose ganglion neurons (5), as well as the binding of 5HT to 5HT 3 and 5HT 4 receptors (6). In addition, chronic treatment of fluoxetine may cause a down-regulation of 5HT 1 receptors (2) and also alter the expression of other receptors, although the latter effects are somewhat controversial (7).…”