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

Henrik Samuel Kohtala, Wiebke Theilmann, Marko Petteri Rosenholm, Heidi K. Müller, Paula Sinikka Kiuru, Gregers Wegener, Jari Tapani Yli-Kauhaluoma, Tomi Pentti Johannes Rantamäki

Research output: Contribution to journalArticlepeer-review

Abstract

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 GSK3 beta (glycogen synthase kinase 3 beta) 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-GSK3 beta signaling alterations during rebound slow EEG (electroencephalogram) oscillations. We investigated here the acute effects of ketamine, 6,6-d(2)-ketamine (a ketamine analogue resistant to metabolism) and cis-HNK that contains (2R,6R) and (2S,6S) enantiomers in 1:1 ratio, on TrkB-GSK3 beta signaling and concomitant electroencephalographic (EEG) alterations in the adult mouse cortex. Ketamine dose-dependently increased slow oscillations and phosphorylations of TrkB(Y816) and GSK3 beta(59) 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-d(2)-ketamine (100 mg/kg, i.p.) recapitulated the effects of ketamine on TrkB and GSK3 beta phosphorylation while cis-HNK at a dose of 20 mg/kg produced negligible acute effects on TrkB-GSK3 beta signaling or slow oscillations. These findings suggest that the acute effects of ketamine on TrkB-GSK3 beta signaling are by no means restricted to subanesthetic (i.e. antidepressant) doses and that cis-HNK is not responsible for these effects.
Original languageEnglish
Article number107684
JournalNeuropharmacology
Volume157
Number of pages9
ISSN0028-3908
DOIs
Publication statusPublished - Oct 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • 3112 Neurosciences
  • Ketamine
  • Sedation
  • Slow oscillations
  • Antidepressant
  • Anesthesia
  • Synaptosomes
  • TRKB NEUROTROPHIN RECEPTOR
  • TREATMENT-RESISTANT DEPRESSION
  • ELECTROCONVULSIVE-THERAPY
  • ANTIDEPRESSANT ACTIONS
  • AMPA RECEPTOR
  • ISOFLURANE-ANESTHESIA
  • PREFRONTAL CORTEX
  • NITROUS-OXIDE
  • S-KETAMINE
  • DELTA-EEG

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