Antidepressants Differentially Regulate Intracellular Signaling from α1-Adrenergic Receptor Subtypes In Vitro

Currently utilized antidepressants have limited effectiveness and frequently incur undesired effects. Most antidepressants are thought to act via the inhibition of monoamine reuptake; however, direct binding to monoaminergic receptors has been proposed to contribute to both their clinical effectiveness and their side effects, or lack thereof. Among the target receptors of antidepressants, alpha 1-adrenergic receptors (ARs) have been implicated in depression etiology, antidepressant action, and side effects. However, differences in the direct effects of antidepressants on signaling from the three subtypes of alpha 1-ARs, namely, alpha 1A-, alpha 1B- and alpha 1D-ARs, have been little explored. We utilized cell lines overexpressing alpha 1A-, alpha 1B- or alpha 1D-ARs to investigate the effects of the antidepressants imipramine (IMI), desipramine (DMI), mianserin (MIA), reboxetine (REB), citalopram (CIT) and fluoxetine (FLU) on noradrenaline-induced second messenger generation by those receptors. We found similar orders of inhibition at alpha 1A-AR (IMI < DMI < CIT < MIA < REB) and alpha 1D-AR (IMI = DMI < CIT < MIA), while the alpha 1B-AR subtype was the least engaged subtype and was inhibited with low potency by three drugs (MIA < IMI = DMI). In contrast to their direct antagonistic effects, prolonged incubation with IMI and DMI increased the maximal response of the alpha 1B-AR subtype, and the CIT of both the alpha 1A- and the alpha 1B-ARs. Our data demonstrate a complex, subtype-specific modulation of alpha 1-ARs by antidepressants of different groups.

Automated summary

The study demonstrated a complex and subtype-specific modulation of alpha 1-adrenergic receptors by different groups of antidepressants.