Modulation of ligand-gated ion channels by antidepressants

The classical concept of the mechanisms of action for most of the available compounds comprises an increase in the concentrations of monoamines in the synaptic cleft by inhibiting monoamine reuptake. This also has consequences for downstream signalling cascades. Moreover, antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), may interfere with the equilibrium of endogenous neuroactive steroids, which are potent allosteric modulators of ligand-gated ion channels, e. g. GABA_A receptors. This may explain in part why antidepressants are also suitable for the treatment of anxiety disorders. Moreover, we could show that different classes of antidepressants (tricyclic antidepressants, SSRIs, selective norepinephrine reuptake inhibitors) are non-competitive functional antagonists at the serotonin type 3 (5-HT₃) receptor, while mirtazapine is a competitive antagonist. The antagonistic effects of antidepressants at the 5-HT₃ receptor did not correlate with their effects on membrane fluidity. The modulation of ligand-gated ion channels such as GABA_A and 5-HT₃ receptors by antidepressants challenges the concept of target specificity of new antidepressant compounds. Moreover, it may constitute a novel pharmacological principle of antidepressants.