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

NEUROPHARMACOLOGY

卷:157

Article

Kohtala, Samuel^1,2,3  Theilmann, Wiebke^1,2  Rosenholm, Marko^1,2,3  Mueller, Heidi K.⁴  Kiuru, Paula⁵  Wegener, Gregers⁴  Yli-Kauhaluoma, Jari⁵  Rantamaki, Tomi^1,2,3 

[1] Univ Helsinki, Lab Neurotherapeut, Mol & Integrat Biosci Res Programme, Fac Biol & Environm Sci, Helsinki, Finland

[2] Univ Helsinki, Div Pharmacol & Pharmacotherapy, Fac Pharm, Drug Res Program, Helsinki, Finland

[3] Univ Helsinki, Fac Med, Sleep Well Res Program, Helsinki, Finland

[4] Aarhus Univ, Dept Clin Med, Translat Neuropsychiat Unit, Aarhus, Denmark

[5] Univ Helsinki, Fac Pharm, Drug Res Program, Div Pharmaceut Chem & Technol, Helsinki, Finland

关键词: Ketamine;    Sedation;    Slow oscillations;    Antidepressant;    Anesthesia;    Synaptosomes;   

DOI  :  10.1016/j.neuropharm.2019.107684

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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