Antidepressants are functional antagonists at the serotonin type 3 (5-HT3) receptor

Abstract

Antidepressants are commonly supposed to enhance serotonergic and/or noradrenergic neurotransmission by inhibition of neurotransmitter reuptake through binding to the respective neurotransmitter transporters or through inhibition of the monoamine oxidase. Using the concentration-clamp technique and measurements of intracellular Ca 2 þ , we demonstrate that different classes of antidepressants act as functional antagonists at the human 5-HT 3A receptor stably expressed in HEK 293 cells and at endogenous 5-HT 3 receptors of rat hippocampal neurons and N1E-115 neuroblastoma cells. The tricyclic antidepressants desipramine, imipramine, and trimipramine, the serotonin reuptake inhibitor fluoxetine, the norepinephrine reuptake inhibitor reboxetine, and the noradrenergic and specific serotonergic antidepressant mirtazapine effectively reduced the serotonin-induced Na þ -and Ca 2 þ -currents in a dose-dependent fashion. This effect was voltage-independent and, with the exception of mirtazapine, noncompetitive. Desipramine, imipramine, trimipramine, and fluoxetine also accelerated receptor desensitization. Moclobemide and carbamazepine had no effect on the serotonin-induced cation current. By analyzing analogues of desipramine and carbamazepine, we found that a basic propylamine side chain increases the antagonistic potency of tricyclic compounds, whereas it is abolished by an uncharged carboxamide group. The antagonistic effects of antidepressants at the 5-HT 3 receptor did not correlate with their effects on membrane fluidity. In conclusion, structurally different types of antidepressants modulate the function of this ligand-gated ion channel. This may represent a yet unrecognized pharmacological principle of antidepressants.

Antidepressants and Antipsychotic Drugs Colocalize with 5-HT3Receptors in Raft-Like Domains

“…After the whole-cell configuration was established, the cells were lifted from the glass substrate and 10 M 5-HT and/or DMI (1 M) was applied using a fast superfusion device. We applied these concentrations because 10 M serotonin were used for the determination of the IC 50 value for the inhibition of the serotonin response by DMI in our previous study (Eisensamer et al, 2003), which was in the low micromolar range.…”

“…This inhibitory action at 5-HT 3 receptors has been observed for both antidepressants (Eisensamer et al, 2003) and antipsychotics (Rammes et al, 2004) independently of their chemical structure and pharmacodynamic properties. With the exception of the known competitive antagonists mirtazapine and clozapine, all of the other antidepressants (Eisensamer et al, 2003) and antipsychotics (Rammes et al, 2004) investigated thus far inhibit the serotonin-induced ion flux through 5-HT 3 receptors in a noncompetitive manner. However, the molecular mechanisms underlying this noncompetitive antagonism have not yet been elucidated.…”

“…Both an indirect modulation of ligand-gated ion channels, e.g., GABA A receptors, via endogenous neuroactive steroids (Uzunov et al, 1996;Romeo et al, 1998;Marx et al, 2003) and a direct modulation of members of this receptor family, e.g., the GABA A receptor (Korpi et al, 1995;Mozrzymas et al, 1999;Malatynska et al, 2000;Robinson et al, 2003) and the 5-HT 3 receptor (Fan, 1994;Breitinger et al, 2001;Eisensamer et al, 2003;Rammes et al, 2004), have been described. This inhibitory action at 5-HT 3 receptors has been observed for both antidepressants (Eisensamer et al, 2003) and antipsychotics (Rammes et al, 2004) independently of their chemical structure and pharmacodynamic properties. With the exception of the known competitive antagonists mirtazapine and clozapine, all of the other antidepressants (Eisensamer et al, 2003) and antipsychotics (Rammes et al, 2004) investigated thus far inhibit the serotonin-induced ion flux through 5-HT 3 receptors in a noncompetitive manner.…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…Recent evidence indicates that SRIs and other antidepressants have 5-HT3-R antagonist properties (Eisensamer et al, 2003(Eisensamer et al, , 2005. Systemic treatment with the 5-HT3-R antagonist ondansetron can augment the antidepressant-like actions of SRIs in the forced swim and tail suspension tests, while the 5-HT3-R agonist 1-(m-chlorophenyl)-biguanide (mCPBG) has the opposite effect (Nakagawa et al, 1998;Redrobe and Bourin, 1997) (cf.…”

Serotonin (5-HT) release in the hippocampus following various conditions and treatments affecting 5-HT receptors has been studied in vivo mainly by the means of brain micro-dialysis: A review

“…Antagonists at 5-HT3 receptors (tropisetron, ondansetron) produced antidepressant-like effects in rodents [23], they may mimic a direct receptor interaction of some clinically effective antidepressants, including fluoxetine, that have been reported to functionally block 5-HT3 receptors [24]. On the other hand, the 5-HT3 receptor agonist 1-( m-Chlorophenyl)-biguanide attenuated the effects of antidepressant compounds in the rat forced swimming test (FST) [25].…”