Ketamine effects on anxiety and fear-related behaviors: Current literature evidence and new findings

Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jun 8:100:109878. doi: 10.1016/j.pnpbp.2020.109878. Epub 2020 Jan 23.


Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, presents a rapid and sustained antidepressant effect in clinical and preclinical studies. Regarding ketamine effects on anxiety, there is a widespread discordance among pre-clinical studies. To address this issue, the present study reviewed the literature (electronic database MEDLINE) to summarize the profile of ketamine effects in animal tests of anxiety/fear. We found that ketamine anxiety/fear-related effects may depend on the anxiety paradigm, schedule of ketamine administration and tested species. Moreover, there was no report of ketamine effects in animal tests of fear related to panic disorder (PD). Based on that finding, we evaluated if treatment with ketamine and another NMDA antagonist, MK-801, would induce acute and sustained (24 hours later) anxiolytic and/or panicolytic-like effects in animals exposed to the elevated T-maze (ETM). The ETM evaluates, in the same animal, conflict-evoked and fear behaviors, which are related, respectively, to generalized anxiety disorder and PD. Male Wistar rats were systemically treated with racemic ketamine (10, 30 and 80 mg/kg) or MK-801 (0.05 and 0.1 mg/kg) and tested in the ETM in the same day or 24 hours after their administration. Ketamine did not affect the behavioral tasks performed in the ETM acutely or 24 h later. MK-801 impaired inhibitory avoidance in the ETM only at 45 min post-injection, suggesting a rapid but not sustained anxiolytic-like effect. Altogether our results suggest that ketamine might have mixed effects in anxiety tests while it does not affect panic-related behaviors.

Keywords: Animal models; Anxiety; Fear; Ketamine; MK-801; Panic.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Anxiety / drug therapy*
  • Anxiety / psychology
  • Avoidance Learning / drug effects
  • Avoidance Learning / physiology
  • Dizocilpine Maleate / pharmacology
  • Dizocilpine Maleate / therapeutic use
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Fear / drug effects*
  • Fear / physiology
  • Fear / psychology*
  • Ketamine / pharmacology
  • Ketamine / therapeutic use*
  • Male
  • Maze Learning / drug effects*
  • Maze Learning / physiology
  • Rats
  • Rats, Wistar


  • Excitatory Amino Acid Antagonists
  • Ketamine
  • Dizocilpine Maleate