Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

Nature. 2018 Feb 14;554(7692):317-322. doi: 10.1038/nature25509.

Abstract

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Affect / drug effects
  • Anhedonia / drug effects
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents / therapeutic use*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channel Blockers / therapeutic use
  • Calcium Channels / metabolism
  • Depression / drug therapy*
  • Disease Models, Animal
  • Habenula / drug effects*
  • Habenula / metabolism*
  • Habenula / pathology
  • Habenula / radiation effects
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Ketamine / therapeutic use*
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Reward
  • Theta Rhythm / drug effects

Substances

  • Antidepressive Agents
  • Calcium Channel Blockers
  • Calcium Channels
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine