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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