Antidepressant Effects of (S)-Ketamine through a Reduction of Hyperpolarization-Activated Current Ih

Chung Sub Kim, Daniel Johnston

Research output: Contribution to journalArticlepeer-review

Abstract

Compelling evidence suggests that a single sub-anesthetic dose of (R,S)-ketamine exerts rapid and robust antidepressant effects. However, the cellular mechanisms underlying the antidepressant effects of (R,S)-ketamine remain unclear. Here, we show that (S)-ketamine reduced dendritic but not somatic hyperpolarization-activated current Ih of dorsal CA1 neurons in unstressed rats, whereas (S)-ketamine decreased both somatic and dendritic Ih in chronic unpredictable stress (CUS) rats. The reduction of Ih by (S)-ketamine was independent of NMDA receptors, barium-sensitive conductances, and cAMP-dependent signaling pathways in both unstressed and CUS groups. (S)-ketamine pretreatment before the onset of depression prevented CUS-induced behavioral phenotypes and neuropathological changes of dorsal CA1 neurons. Finally, in vivo infusion of thapsigargin-induced anxiogenic- and anhedonic-like behaviors and upregulation of functional Ih, but these were reversed by (S)-ketamine. Our results suggest that (S)-ketamine reduces or prevents Ih from being increased following CUS, which contributes to the rapid antidepressant effects and resiliency to CUS.

Original languageEnglish (US)
Article number101239
JournaliScience
Volume23
Issue number6
DOIs
StatePublished - Jun 26 2020
Externally publishedYes

Keywords

  • Behavioral Neuroscience
  • Cellular Neuroscience
  • Neuroscience

ASJC Scopus subject areas

  • General

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