(2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray

Neuropharmacology. 2018 Sep 1;139:1-12. doi: 10.1016/j.neuropharm.2018.06.033. Epub 2018 Jun 25.


It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG.

Keywords: AMPA receptor; Chronic stress; Depression; Electrophysiology; Periaqueductal gray.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / poisoning*
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / physiopathology
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Glutamic Acid / metabolism
  • Helplessness, Learned
  • Ketamine / analogs & derivatives*
  • Ketamine / pharmacology
  • Male
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Periaqueductal Gray / drug effects*
  • Periaqueductal Gray / metabolism
  • Rats, Sprague-Dawley
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism
  • Stress, Psychological / drug therapy
  • Stress, Psychological / physiopathology
  • Synapses / drug effects
  • Synapses / metabolism
  • Tissue Culture Techniques


  • Antidepressive Agents
  • Receptors, AMPA
  • Glutamic Acid
  • Ketamine
  • 6-hydroxynorketamine
  • glutamate receptor ionotropic, AMPA 1