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.
Highlights
IntroductionTrazodone is an antidepressant drug that, in addition to its inhibitory activity at cell membrane 5-HT1A receptor (5-HT) transporter (SERT), is a competitive ligand at 5-HT1A 5-HT2A, 5-HT2C receptors and α1-adrenoceptors for which it displays considerable affinity [5, 6]
The brain serotonin (5-HT) system modulates a variety of brain functions including mood, cognition, emotional behaviour, and sleep [1, 2, 3] and its dysregulation appears to contribute in related psychopathological states such as depression, anxiety, impulsivity and aggression [4].Trazodone is an antidepressant drug that, in addition to its inhibitory activity at cell membrane 5-HT1A receptor (5-HT) transporter (SERT), is a competitive ligand at 5-HT1A 5-HT2A, 5-HT2C receptors and α1-adrenoceptors for which it displays considerable affinity [5, 6]
Application of trazodone produced a concentration-dependent inhibition of dorsal raphe nucleus (DRN) serotonergic neuron activity facilitated by 10 μM PE in standard artificial cerebrospinal fluid (ACSF) (Fig 1A and 1B)
Summary
Trazodone is an antidepressant drug that, in addition to its inhibitory activity at cell membrane 5-HT transporter (SERT), is a competitive ligand at 5-HT1A 5-HT2A, 5-HT2C receptors and α1-adrenoceptors for which it displays considerable affinity [5, 6] These pharmacological properties have been suggested to contribute a favourable safety profile such as facilitation of sleep and reduced sexual dysfunction [7], the direct effects of trazodone on serotoninergic neuron activity are still not adequately known for modelling the possible pharmacological mechanisms underlying the therapeutic action(s) of the drug. Increased extracellular 5-HT in raphe nuclei acutely produced by block of SERT results in (auto)inhibition of serotonergic neuron activity and in reduction of 5-HT release in projection brain areas This is believed to delay the onset of antidepressant therapeutic effect until subsensitivity of 5-HT1AARs develops to weaken the autoinhibitory feedback [13, 14]. On the basis of this notion it has been proposed that the association of 5 HT1A receptor antagonists could hasten the response to monoamine uptake blockers [15, 16, 17] and, more recently, that antidepressant drugs with partial agonist property at 5 HT1A receptors could display faster onset of therapeutic response [18]
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