Physiological basis underlying antidepressant-induced activation of TrkB receptors
Physiological basis underlying antidepressant-induced activation of TrkB receptors
Summary We show that both pharmacological and non-pharmacological treatments of depression activate TrkB receptors—a well-established target of antidepressants—by inducing a physiological response coupled to sedation. Several rapid-acting antidepressants trigger TrkB signaling by evoking a state associated with electroencephalographic slow-wave activity, behavioral immobility, reduced cerebral glucose utilization, and lowered body temperature. Remarkably, antidepressant-induced TrkB signaling was not compromised in animals exhibiting reduced activity-dependent release of BDNF but was diminished by maintaining animals in warm ambient temperature. Most importantly, prevention of the hypothermic response attenuated the behavioral effects produced by rapid-acting antidepressant nitrous oxide. Our results suggest that the phenomenon underlying TrkB transactivation—changes in energy expenditure and thermoregulation—is essential, but not sufficient, for antidepressant responses. Indeed, regardless of differential clinical and pharmacodynamic properties, all drugs that disrupt energy metabolism and induce hypothermia activated TrkB. This study challenges pharmacology-centric hypotheses regarding antidepressant effects and highlight the role of complex changes in bioenergetics and thermoregulation. HighlightsRapid-acting antidepressants evoke homeostatic emergence of slow-wave sleep during which TrkB signaling becomes regulated.Non-antidepressant metabolic inhibitors and diverse sedatives activate TrkB signaling.Reduction in body temperature determined the ability of antidepressants to transactivate TrkB.Drug-induced TrkB signaling was blunted by maintenance of normothermic body temperature.Warm ambient temperature after nitrous oxide exposure blocked the antidepressant-like effects. Graphical abstractbiorxiv;2021.08.30.458151v1/UFIG1F1ufig1
Alitalo Okko、Saarreharju Roosa、Matsui Nobuaki、Rantam?ki Tomi、Kohtala Piia、Kohtala Samuel、Sarparanta Mirkka、Hernandez Gemma Gonzalez、M¨1ller Heidi Kaastrup、Rosenholm Marko、K?rkk?inen Olli、Klein Anders、Rozov Stanislav、Theilmann Wiebke
Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of HelsinkiLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of HelsinkiFaculty of Pharmaceutical Sciences, Tokushima Bunri UniversityLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of HelsinkiLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of Helsinki||Feil Family Brain and Mind Research Institute, Department of Psychiatry, Weill Cornell MedicineLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of Helsinki||Feil Family Brain and Mind Research Institute, Department of Psychiatry, Weill Cornell MedicineDepartment of Chemistry, University of HelsinkiLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of HelsinkiTranslational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus UniversityLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of Helsinki||Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of CopenhagenSchool of Pharmacy, University of Eastern Finland||Afekta Technologies LtdNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen||Department of Drug Design & Pharmacology, University of CopenhagenLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki||SleepWell Research Program, Faculty of Medicine, University of HelsinkiLaboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki
基础医学神经病学、精神病学生理学
antidepressantenergy metabolismhypothermianitrous oxidephysiologyrapid-acting antidepressantreceptor pharmacologysedationsleepsleep deprivation
Alitalo Okko,Saarreharju Roosa,Matsui Nobuaki,Rantam?ki Tomi,Kohtala Piia,Kohtala Samuel,Sarparanta Mirkka,Hernandez Gemma Gonzalez,M¨1ller Heidi Kaastrup,Rosenholm Marko,K?rkk?inen Olli,Klein Anders,Rozov Stanislav,Theilmann Wiebke.Physiological basis underlying antidepressant-induced activation of TrkB receptors[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.08.30.458151.点此复制
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