Many mechanisms have been proposed to explain acute antidepressant
drug-induced activation of TrkB neurotrophin receptors, but several
questions remain. In a series of pharmacological experiments, we observed
that TrkB activation induced by antidepressants and several other
drugs correlated with sedation, and most importantly, coinciding hypothermia.
Untargeted metabolomics of pharmacologically dissimilar TrkB activating
treatments revealed effects on shared bioenergetic targets involved
in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating
a common perturbation in metabolic activity. Both activation of TrkB
signaling and hypothermia were recapitulated by administration of
inhibitors of glucose and lipid metabolism, supporting a close relationship
between metabolic inhibition and neurotrophic signaling. Drug-induced
TrkB phosphorylation was independent of electroencephalography slow-wave
activity and remained unaltered in knock-in mice with the brain-derived
neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent
BDNF release, alluding to an activation mechanism independent from
BDNF and neuronal activity. Instead, we demonstrated that the active
maintenance of body temperature prevents activation of TrkB and other
targets associated with antidepressants, including p70S6 kinase downstream
of the mammalian target of rapamycin (mTOR) and glycogen synthase
kinase 3β (GSK3β). Increased TrkB, GSK3β, and p70S6K
phosphorylation was also observed during recovery sleep following
sleep deprivation, when a physiological temperature drop is known
to occur. Our results suggest that the changes in bioenergetics and
thermoregulation are causally connected to TrkB activation and may
act as physiological regulators of signaling processes involved in
neuronal plasticity.