Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptors

Biol Psychiatry. 2008 Feb 15;63(4):349-52. doi: 10.1016/j.biopsych.2007.05.028. Epub 2007 Jul 23.

Abstract

Background: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action.

Methods: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput.

Results: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors.

Conclusions: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Depressive Disorder, Major / drug therapy*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Helplessness, Learned
  • Hippocampus / drug effects
  • Hippocampus / pathology*
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use
  • Male
  • Mice
  • Phosphorylation / drug effects
  • Psychomotor Performance / drug effects
  • Receptors, AMPA / drug effects
  • Swimming
  • Time Factors
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / metabolism*

Substances

  • Excitatory Amino Acid Antagonists
  • Receptors, AMPA
  • Ketamine
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • glutamate receptor ionotropic, AMPA 1