Open AccessDual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and α1-adrenoceptor antagonism
Author(s) -
Alberto Montalbano,
Boris Mlinar,
Francesco Bonfiglio,
Lorenzo Polenzani,
M. Magnani,
Renato Corradetti
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0222855
Subject(s) - trazodone , agonist , dorsal raphe nucleus , phenylephrine , partial agonist , serotonergic , chemistry , pharmacology , raphe nuclei , prazosin , serotonin , antagonist , 5 ht receptor , intrinsic activity , receptor , medicine , endocrinology , antidepressant , biology , biochemistry , hippocampus , blood pressure
Trazodone is an antidepressant drug with considerable affinity for 5-HT 1A receptors and α 1 -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-HT 1A receptors (5-HT 1A ARs) and α 1 -adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α 1 -adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α 1 -adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1–10 μM) concentration-dependently silenced neurons through activation of 5-HT 1A ARs. The effect was fully antagonized by the selective 5-HT 1A receptor antagonist Way-100635. With 5-HT 1A 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 α 1 -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-HT 1A ARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT 1A AR-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-HT 1A ARs and disfacilitation of firing through α 1 -adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α 1 -adrenoceptor stimulation.