KCNQ channel openers reverse depressive symptoms via an active resilience mechanism

Nat Commun. 2016 May 24;7:11671. doi: 10.1038/ncomms11671.

Abstract

Less than half of patients suffering from major depressive disorder, a leading cause of disability worldwide, achieve remission with current antidepressants, making it imperative to develop more effective treatment. A new therapeutic direction is emerging from the increased understanding of natural resilience as an active stress-coping process. It is known that potassium (K(+)) channels in the ventral tegmental area (VTA) are an active mediator of resilience. However, no druggable targets have been identified to potentiate active resilience mechanisms. In the chronic social defeat stress model of depression, we report that KCNQ-type K(+) channel openers, including FDA-approved drug retigabine (ezogabine), show antidepressant efficacy. We demonstrate that overexpression of KCNQ channels in the VTA dopaminergic neurons and either local infusion or systemic administration of retigabine normalized neuronal hyperactivity and depressive behaviours. These findings identify KCNQ as a target for conceptually novel antidepressants that function through the potentiation of active resilience mechanisms.

Publication types

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

MeSH terms

  • Adaptation, Psychological / drug effects
  • Adaptation, Psychological / physiology
  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology
  • Carbamates / pharmacology
  • Carbamates / therapeutic use
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / metabolism
  • Depressive Disorder, Major / physiopathology
  • Depressive Disorder, Major / psychology
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Electrophysiological Phenomena
  • Humans
  • KCNQ3 Potassium Channel / metabolism*
  • Male
  • Membrane Transport Modulators / pharmacology*
  • Membrane Transport Modulators / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Phenylenediamines / pharmacology
  • Phenylenediamines / therapeutic use
  • Resilience, Psychological / drug effects*
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / metabolism
  • Stress, Psychological / psychology
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism
  • Ventral Tegmental Area / physiology

Substances

  • Antidepressive Agents
  • Carbamates
  • KCNQ3 Potassium Channel
  • Kcnq3 protein, mouse
  • Membrane Transport Modulators
  • Phenylenediamines
  • ezogabine