Pharmacopsychiatry 2003; 36 - 66
DOI: 10.1055/s-2003-825317

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

B Eisensamer 1, 2, G Rammes 1, G Gimpl 3, M Shapa 2, U Ferrari 1, G Hapfelmeier 4, B Bondy 2, C Parsons 5, K Gilling 5, W Zieglgänsberger 1, F Holsboer 1, R Rupprecht 1, 2
  • 1Max-Planck-Institute of Psychiatry, Munich, Germany
  • 2Department of Psychiatry, Ludwig-Maximilians-Universität, Munich, Germany
  • 3Institute of Biochemistry, Johannes-Gutenberg-Universität, Mainz, Germany
  • 4Department of Anaesthesiology, Technische Universität München, Munich, Germany
  • 5Merz Pharmaceuticals, Frankfurt, Germany

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 Ca2+ we demonstrate that different classes of antidepressants act as functional antagonists at the 5-HT3A receptor. The tricyclic antidepressants desipramine, imipramine and trimipramine, the SSRI fluoxetine, the SNARI reboxetine, and the NaSSA mirtazapine effectively reduced the serotonin-induced Na+- and Ca2+-currents in a dose-dependent fashion. This effect was voltage-independent and, with the exception of mirtazapine, non-competitive. 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. 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.