| First Author | Montalbano A | Year | 2019 |
| Journal | PLoS One | Volume | 14 |
| Issue | 9 | Pages | e0222855 |
| PubMed ID | 31557210 | Mgi Jnum | J:280043 |
| Mgi Id | MGI:6364087 | Doi | 10.1371/journal.pone.0222855 |
| Citation | Montalbano A, et al. (2019) Dual inhibitory action of trazodone on dorsal raphe serotonergic neurons through 5-HT1A receptor partial agonism and alpha1-adrenoceptor antagonism. PLoS One 14(9):e0222855 |
| abstractText | Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and alpha1-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 alpha1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at alpha1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective alpha1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1-10 muM) 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 muM) concentration-dependently inhibited neuron firing facilitated by 1 muM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10-100 muM) indicated competitive antagonism at alpha1-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 alpha1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of alpha1-adrenoceptor stimulation. |
