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.
Highlights
Rapid-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.
Competing Interest Statement
W.T., T.R. and S.K. are listed as co-inventors on a patent wherein new EEG-based tools enabling the development of rapid-acting antidepressants and the efficacy monitors thereof are disclosed. W.T., T.R. and S.K. have assigned their patent rights to the University of Helsinki but will share a percentage of any royalties that may be received by the University of Helsinki.