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bioRxiv · 10.1101/2021.08.30.458151

Physiological basis underlying antidepressant-induced activation of TrkB receptors

Alitalo, O.·Kohtala, S.·Rosenholm, M.·Kohtala, P.·Saarreharju, R.·Matsui, N.·Gonzalez Hernandez, G.·Kaastrup Muller, H.·Theilmann, W.·Sarparanta, M.·Klein, A.·Karkkainen, O.·Rozov, S.·Rantamaki, T.
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Abstract

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. HighlightsO_LIRapid-acting antidepressants evoke homeostatic emergence of slow-wave sleep during which TrkB signaling becomes regulated. C_LIO_LINon-antidepressant metabolic inhibitors and diverse sedatives activate TrkB signaling. C_LIO_LIReduction in body temperature determined the ability of antidepressants to transactivate TrkB. C_LIO_LIDrug-induced TrkB signaling was blunted by maintenance of normothermic body temperature. C_LIO_LIWarm ambient temperature after nitrous oxide exposure blocked the antidepressant-like effects. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/458151v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@1f7351borg.highwire.dtl.DTLVardef@bf920forg.highwire.dtl.DTLVardef@10e34eaorg.highwire.dtl.DTLVardef@1b42bb6_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Alitalo, O., Kohtala, S., Rosenholm, M., Kohtala, P., Saarreharju, R., Matsui, N., Gonzalez Hernandez, G., Kaastrup Muller, H., Theilmann, W., Sarparanta, M., Klein, A., Karkkainen, O., Rozov, S., Rantamaki, T.. 2021-08-31. Physiological basis underlying antidepressant-induced activation of TrkB receptors. https://doi.org/10.1101/2021.08.30.458151

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