Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and α1-adrenoceptor antagonism

PLoS One. 2019 Sep 26;14(9):e0222855. doi: 10.1371/journal.pone.0222855. eCollection 2019.

Abstract

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1-10 μM) concentration-dependently silenced neurons through activation of 5-HT1AARs. The effect was fully antagonized by the selective 5-HT1A receptor antagonist Way-100635. With 5-HT1A receptors blocked by Way-100635, trazodone (1-10 μM) concentration-dependently inhibited neuron firing facilitated by 1 μM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10-100 μM) indicated competitive antagonism at α1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2-/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT1AARs and disfacilitation of firing through α1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α1-adrenoceptor stimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / pharmacology*
  • Animals
  • Antidepressive Agents / pharmacology*
  • Dorsal Raphe Nucleus / cytology
  • Dorsal Raphe Nucleus / drug effects*
  • Dorsal Raphe Nucleus / metabolism
  • Dose-Response Relationship, Drug
  • Male
  • Mice
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Phenylephrine / pharmacology
  • Piperazines / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Receptor, Serotonin, 5-HT1A / metabolism
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Serotonergic Neurons / drug effects*
  • Serotonergic Neurons / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Trazodone / pharmacology*
  • Tryptophan Hydroxylase / genetics

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Antidepressive Agents
  • Piperazines
  • Pyridines
  • Receptors, Adrenergic, alpha-1
  • Serotonin 5-HT1 Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • Phenylephrine
  • N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
  • Tph2 protein, mouse
  • Tryptophan Hydroxylase
  • Trazodone

Grants and funding

This study was funded by Angelini S.p.A., by grant number 039RD15382 awarded to Prof. Renato Corradetti. The funder provided support in the form of salaries for authors L.P and M.M., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.