Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex

Eur Psychiatry. 2014 Sep;29(7):419-23. doi: 10.1016/j.eurpsy.2013.10.005. Epub 2013 Dec 8.

Abstract

Ketamine exerts fast acting, robust, and lasting antidepressant effects in a sub-anesthetic dose, however, the underlying mechanisms are still not fully elucidated. Recent studies have suggested that ketamine's antidepressant effects are probably attributed to the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The present study aimed to observe the effects of AMPA receptor modulators on mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) expression during the procedure of ketamine exerting antidepressant effects. Therefore, we pretreated rats with NBQX, an AMPA receptor antagonist, or CX546, an AMPA receptor agonist, and subsequently observed the immobility time during the forced swimming test (FST) and the hippocampal and prefrontal cortical levels of mTOR and BDNF. The results showed ketamine decreased the immobility time of rats during the FST and increased the hippocampal and prefrontal cortical mTOR and BDNF. NBQX pretreatment significantly increased the immobility time and decreased the levels of mTOR and BDNF when compared with vehicle 1 (DMSO) pretreatment. CX546 pretreatment significantly decreased the immobility time and increased the levels of mTOR and BDNF when compared with vehicle 2 (DMSO+ethanol) pretreatment. Our results suggest ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.

Keywords: Brain-derived neurotrophic factor; Depression; Ketamine; Mammalian target of rapamycin; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain-Derived Neurotrophic Factor / drug effects*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Dioxoles / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Ketamine / pharmacology*
  • Piperidines / pharmacology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / metabolism
  • Quinoxalines / pharmacology
  • Rats
  • Receptors, AMPA / drug effects*
  • Receptors, AMPA / metabolism
  • TOR Serine-Threonine Kinases / drug effects*
  • TOR Serine-Threonine Kinases / metabolism
  • Up-Regulation / drug effects

Substances

  • 1-(1,4-benzodioxan-6-ylcarbonyl)piperidine
  • Antidepressive Agents
  • Brain-Derived Neurotrophic Factor
  • Dioxoles
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Piperidines
  • Quinoxalines
  • Receptors, AMPA
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Ketamine
  • TOR Serine-Threonine Kinases
  • mTOR protein, rat