Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT(1A) receptor partial agonism and α(1)-adrenoceptor antagonism

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.