Abstract
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, α1‑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 α1-ARs, namely, α1A-, α1B- and α1D‑ARs, have been little explored. We utilized cell lines overexpressing α1A-, α1B- or α1D-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 α1A-AR (IMI < DMI < CIT < MIA < REB) and α1D‑AR (IMI = DMI < CIT < MIA), while the α1B-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 α1B-AR subtype, and the CIT of both the α1A- and the α1B-ARs. Our data demonstrate a complex, subtype-specific modulation of α1-ARs by antidepressants of different groups.
Highlights
Members of a prototypical class of antidepressants, the tricyclic antidepressants (TCAs), simultaneously inhibit noradrenaline reuptake and antagonize specific noradrenergic receptors, which may lead to self-cancelling actions [3,5,6,7,8]
We show that prolonged incubation with imipramine and desipramine increases the maximal response to α1B-adrenergic receptors (ARs), while citalopram increases the maximal response to the α1A subtype and, to a lesser extent, the α1B subtype
The generated cell lines were validated by measuring the response to the agonists noradrenaline and phenylephrine (Figure 1D,E). α1A-AR showed an EC50 of 1 × 10−6.2 for noradrenaline and an EC50 of 1 × 10−6.1 (Figure 1D) for phenylephrine, while α1B-AR
Summary
Depression is a debilitating disorder causing lasting suffering in millions of people, reducing their ability to live normal lives and representing a major, often hidden, burden to society. It is estimated that more than 300 million people suffer from depression worldwide [1]; for example, in Europe, depression is the most prevalent mental disorder, affecting more than 30 million people each year [2]. It is apparent that apart from modulating the synaptic levels of serotonin, noradrenaline and dopamine by altering their reuptake or metabolism, many antidepressants can directly bind to the receptors of these monoamines. Members of a prototypical class of antidepressants, the tricyclic antidepressants (TCAs), simultaneously inhibit noradrenaline reuptake and antagonize specific noradrenergic receptors, which may lead to self-cancelling actions [3,5,6,7,8]. Antagonistic properties might shape the actual profile of the receptor activation
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