RESUMEN
The multimodal antidepressant vortioxetine is thought to mediate its pharmacological effects via 5-HT1A receptor agonism, 5-HT1B receptor partial agonism, 5-HT1D, 5-HT3, 5-HT7 receptor antagonism and 5-HT transporter inhibition. Here we studied vortioxetine's functional effects across species (canine, mouse, rat, guinea pig and human) in cellular assays with heterologous expression of 5-HT3A receptors (in Xenopus oocytes and HEK-293 cells) and in mouse neuroblastoma N1E-115 cells with endogenous expression of 5-HT3A receptors. Furthermore, we studied the effects of vortioxetine on activity of CA1 Stratum Radiatum interneurons in rat hippocampus slices using current- and voltage-clamping methods. The patched neurons were subsequently filled with biocytin for confirmation of 5-HT3 receptor mRNA expression by in situ hybridization. Whereas, both vortioxetine and the 5-HT3 receptor antagonist ondansetron potently antagonized 5-HT-induced currents in the cellular assays, vortioxetine had a slower off-rate than ondansetron in oocytes expressing 5-HT3A receptors. Furthermore, vortioxetine's but not ondansetron's 5-HT3 receptor antagonistic potency varied considerably across species. Vortioxetine had the highest potency at rat and the lowest potency at guinea pig 5-HT3A receptors. Finally, in 5-HT3 receptor-expressing GABAergic interneurons from the CA1 stratum radiatum, vortioxetine and ondansetron blocked depolarizations induced by superfusion of either 5-HT or the 5-HT3 receptor agonist mCPBG. Taken together, these data add to a growing literature supporting the idea that vortioxetine may inhibit GABAergic neurotransmission in some brain regions via a 5-HT3 receptor antagonism-dependent mechanism and thereby disinhibit pyramidal neurons and enhance glutamatergic signaling.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antidepresivos/farmacología , Interneuronas/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Vortioxetina/farmacología , Potenciales de Acción/fisiología , Animales , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Perros , Ácido Glutámico/metabolismo , Cobayas , Células HEK293 , Humanos , Interneuronas/metabolismo , Ratones , Ondansetrón/farmacología , Oocitos , Células Piramidales/metabolismo , Ratas , Receptores de Serotonina 5-HT3/metabolismo , Serotonina/metabolismo , Técnicas de Cultivo de Tejidos , Xenopus laevis , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We investigated the effects of Ginkgo biloba extract (GBE) and ginkgolide (GLD) on human ether-a-go-go-related gene (hERG)-encoded K(+) channels and its underlying mechanisms in the hERG-HEK293 cell line by determining GBE- and GLD-induced changes in action potential duration (APD), L-type calcium currents (ICa-L), and the intracellular calcium concentration ([Ca(2+)]i) in guinea-pig ventricular myocytes. hERG currents, APD and ICa-L were recorded using the whole-cell patch clamp technique, the [Ca(2+)]i was examined by an immunofluorescence experiment. In the present study, we found that a low concentration of GBE (0.005 mg/ml) increased hERG currents, but the high concentration of GBE (from 0.05 to 0.25 mg/ml) reduced hERG currents. GLD reduced hERG currents in a concentration-dependent manner (from 0.005 to 0.25 mg/ml). Both GBE and GLD altered kinetics of the hERG channel. GBE accelerated the activation of hERG channels without changing the inactivation curve, but reduced the time constant of inactivation; GLD did not shift the activation or the inactivation curve, but only reduced the time constant of inactivation. Both GBE and GLD shortened the APD, inhibited the ICa-L currents, and decreased the [Ca(2+)]i in isolated guinea-pig ventricular myocytes. The results indicate that GBE and GLD can prevent ischemic arrhythmias and have an antiarrhythmic effect potential via inhibition of IKr and ICa-L currents.