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Neuropharmacology Volume 157, October 2019, 107684,


Ketamine-induced regulation of TrkB-GSK3β signaling is accompanied by slow EEG oscillations and sedation but is independent of hydroxynorketamine metabolites

Kohtala S, Theilmann W, Rosenholm M, Müller H, Kiuru P, Wegener G, Yli-Kauhaluoma J, Rantamäki T


Subanesthetic rather than anesthetic doses are thought to bring the rapid antidepressant effects of the NMDAR (N-methyl-d-aspartate receptor) antagonist ketamine. Among molecular mechanisms, activation of BDNF receptor TrkB along with the inhibition of GSK3β (glycogen synthase kinase 3β) are considered as critical molecular level determinants for ketamine’s antidepressant effects. Hydroxynorketamines (2R,6R)-HNK and (2S,6S)–HNK), non-anesthetic metabolites of ketamine, have been proposed to govern the therapeutic effects of ketamine through a mechanism not involving NMDARs. However, we have shown that nitrous oxide, another NMDAR blocking anesthetic and a putative rapid-acting antidepressant, evokes TrkB-GSK3β signaling alterations during rebound slow EEG (electroencephalogram) oscillations. We investigated here the acute effects of ketamine, 6,6-d2-ketamine (a ketamine analogue resistant to metabolism) and cis-HNK that contains (2R,6R) and (2S,6S) enantiomers in 1:1 ratio, on TrkB-GSK3β signaling and concomitant electroencephalographic (EEG) alterations in the adult mouse cortex. Ketamine dose-dependently increased slow oscillations and phosphorylations of TrkBY816 and GSK3βS9 in crude brain homogenates (i.e. sedative/anesthetic doses (>50 mg/kg, i.p.) produced more prominent effects than a subanesthetic dose (10 mg/kg, i.p.)). Similar, albeit less obvious, effects were seen in crude synaptosomes. A sedative dose of 6,6-d2-ketamine (100 mg/kg, i.p.) recapitulated the effects of ketamine on TrkB and GSK3β phosphorylation while cis-HNK at a dose of 20 mg/kg produced negligible acute effects on TrkB-GSK3β signaling or slow oscillations. These findings suggest that the acute effects of ketamine on TrkB-GSK3β signaling are by no means restricted to subanesthetic (i.e. antidepressant) doses and that cis-HNK is not responsible for these effects.