Efectos de antidepresivos de uso en clínica sobre los receptores nicotínicos neuronales de acetilcolina

  1. Gameiro Ros, Isabel María
unter der Leitung von:
  1. Luis Gandía Juan Doktorvater/Doktormutter
  2. J. M. Hernández Guijo Doktorvater/Doktormutter

Universität der Verteidigung: Universidad Autónoma de Madrid

Fecha de defensa: 14 von Juni von 2019

Gericht:
  1. Antonio García García Präsident/in
  2. Francisco Javier Egea Maiquez Sekretär/in
  3. Elisa Navarro González de Mesa Vocal
  4. Jonathan Rojo Ruiz Vocal
  5. Victoria Maneu Flores Vocal

Art: Dissertation

Zusammenfassung

The intricacy that characterizes the physiopathology of depression, a matter that has not been yet fully elucidated, has motivated the postulation of diverse theories aiming to explain the mechanisms underlying the development of the disease. The monoaminergic theory, that considers the lowered levels of serotonin and noradrenaline the cause of depressive symptoms, has been the prevailing one through the years, and the compass guiding the development of antidepressant drugs. Nevertheless, the drawbacks of current treatments have turned the attention towards alternative theories, among which the cholinergic theory of depression outlines. This theory attributes the cause of the disease to a hyperactivity of the cholinergic neurotransmission over the noradrenergic one, and has been gaining relevance due to the increasing volume of evidences that support it, and to its tight relationship with other hypothesis of depression. On the basis of these facts, in this Thesis we have contemplated the study of the potential ability of the antidepressants duloxetine, sertraline, reboxetine, mirtazapine and moclobemide, currently used in clinical practice, to exert an antagonism on the neuronal nicotinic acetylcholine receptor (nAChR). We have assessed this study by means of the bovine chromaffin cell as a neurotransmission and neurosecretion model, and we have evaluated the effects of these five drugs on processes that are subsequent to the activation of nAChRs in these cells, such as: catecholamine exocytosis, cytosolic calcium signals, and nicotinic currents. In addition, we have studied the effects of these drugs on sodium and calcium channels in these cells, as well as on specific subtypes of human nAChRs, to determine the selectivity of the blockade exerted. The results indicate that duloxetine, sertraline and reboxetine are neuronal nAChRs antagonists, given that they have notably blocked the three cellular events mentioned, all of them subsequent to nAChR activation in chromaffin cells. Moreover, they have blocked specific subtypes of human nAChRs, showing different selectivity. The contradictory results obtained with mirtazapine do not allow us to state that it is a nicotinic antagonist, while moclobemide has not demonstrated to block neuronal nAChRs. The findings of this Thesis might be helpful in shedding some light on the numerous questions regarding the physiopathology of depression, as well as in the better understanding of the mechanism of action of current drugs, pointing to new pathways towards the development of more effective antidepressants.