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 - 25 Jun 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

Cite this

@article{a8b89f5914624940a5f7c1c652e3088c,
title = "Ketamine-induced regulation of TrkB-GSK3β signaling is accompanied by slow EEG oscillations and sedation but is independent of hydroxynorketamine metabolites",
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.",
keywords = "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",
author = "Kohtala, {Henrik Samuel} and Wiebke Theilmann and Rosenholm, {Marko Petteri} and M{\"u}ller, {Heidi K.} and Kiuru, {Paula Sinikka} and Gregers Wegener and Yli-Kauhaluoma, {Jari Tapani} and Rantam{\"a}ki, {Tomi Pentti Johannes}",
year = "2019",
month = "6",
day = "25",
doi = "10.1016/j.neuropharm.2019.107684",
language = "English",
volume = "157",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Scientific Publ. Co",

}

TY - JOUR

T1 - Ketamine-induced regulation of TrkB-GSK3β signaling is accompanied by slow EEG oscillations and sedation but is independent of hydroxynorketamine metabolites

AU - Kohtala, Henrik Samuel

AU - Theilmann, Wiebke

AU - Rosenholm, Marko Petteri

AU - Müller, Heidi K.

AU - Kiuru, Paula Sinikka

AU - Wegener, Gregers

AU - Yli-Kauhaluoma, Jari Tapani

AU - Rantamäki, Tomi Pentti Johannes

PY - 2019/6/25

Y1 - 2019/6/25

N2 - 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.

AB - 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.

KW - 317 Pharmacy

KW - 3112 Neurosciences

KW - Ketamine

KW - Sedation

KW - Slow oscillations

KW - Antidepressant

KW - Anesthesia

KW - Synaptosomes

KW - TRKB NEUROTROPHIN RECEPTOR

KW - TREATMENT-RESISTANT DEPRESSION

KW - ELECTROCONVULSIVE-THERAPY

KW - ANTIDEPRESSANT ACTIONS

KW - AMPA RECEPTOR

KW - ISOFLURANE-ANESTHESIA

KW - PREFRONTAL CORTEX

KW - NITROUS-OXIDE

KW - S-KETAMINE

KW - DELTA-EEG

U2 - 10.1016/j.neuropharm.2019.107684

DO - 10.1016/j.neuropharm.2019.107684

M3 - Article

VL - 157

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

M1 - 107684

ER -