Rapid‐acting antidepressants and the regulation of TrkB neurotrophic signalling—Insights from ketamine, nitrous oxide, seizures and anaesthesia

Abstract

Increased glutamatergic neurotransmission and synaptic plasticity in the prefrontal cortex have been associated with the rapid antidepressant effects of ketamine. Activation of BDNF (brain‐derived neurotrophic factor) receptor TrkB is considered a key molecular event for antidepressant‐induced functional and structural synaptic plasticity. Several mechanisms have been proposed to underlie ketamine's effects on TrkB, but much remains unclear. Notably, preliminary studies suggest that besides ketamine, nitrous oxide (N2O) can rapidly alleviate depressive symptoms. We have shown nitrous oxide to evoke TrkB signalling preferentially after the acute pharmacological effects have dissipated (ie after receptor disengagement), when slow delta frequency electroencephalogram (EEG) activity is up‐regulated. Our findings also demonstrate that various anaesthetics and sedatives activate TrkB signalling, further highlighting the complex mechanisms underlying TrkB activation. We hypothesize that rapid‐acting antidepressants share the ability to regulate TrkB signalling during homeostatically evoked slow‐wave activity and that this mechanism is important for sustained antidepressant effects. Our observations urge the examination of rapid and sustained antidepressant effects beyond conventional receptor pharmacology by focusing on brain physiology and temporally distributed signalling patterns spanning both wake and sleep. Potential implications of this approach for the improvement of current therapies and discovery of novel antidepressants are discussed.

Linking Hypothermia and Altered Metabolism with TrkB Activation

“…28−30 Collectively, emerging evidence suggests that antidepressantinduced TrkB activation may not involve a straightforward ligand release and/or receptor binding mechanism but could instead be associated with some components of the physiological state evoked by the pharmacological treatment. 31 This response, besides being characterized by EEG slowing and neurotrophic signaling, co-associates with other physiological changes connected with deep slow-wave sleep: behavioral immobility, 32 attenuated brain energy expenditure, 33 and reduced body temperature. 34 Here, we present evidence from molecular studies in mice showing that a range of pharmacological agents possessing sedative properties can activate neurotrophic signaling irrespective of their primary pharmacological target.…”