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

Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and a alpha(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-HT1A receptors (5-HT(1A)ARs) and alpha(1)-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at alpha(1)-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective alpha(1)-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1-10 mu M) 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 mu M) concentration-dependently inhibited neuron firing facilitated by 1 mu M phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10-100 mu M) indicated competitive antagonism at alpha(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 (similar to 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 alpha(1)-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of alpha(1)-adrenoceptor stimulation.