The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity?

Neurosci Biobehav Rev. 2015 May;52:193-206. doi: 10.1016/j.neubiorev.2015.03.005. Epub 2015 Mar 14.


Depression is a major psychiatric disorder affecting more than 120 million people worldwide every year. Changes in monoaminergic transmitter release are suggested to take part in the pathophysiology of depression. However, more recent experimental evidence suggests that glutamatergic mechanisms might play a more central role in the development of this disorder. The importance of the glutamatergic system in depression was particularly highlighted by the discovery that N-methyl-D-aspartate (NMDA) receptor antagonists (particularly ketamine) exert relatively long-lasting antidepressant like effects with rapid onset. Importantly, the antidepressant-like effects of NMDA receptor antagonists, but also other antidepressants (both classical and novel), require activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Additionally, expression of AMPA receptors is altered in patients with depression. Moreover, preclinical evidence supports an important involvement of AMPA receptor-dependent signaling and plasticity in the pathophysiology and treatment of depression. Here we summarize work published on the involvement of AMPA receptors in depression and discuss a possible central role for AMPA receptors in the pathophysiology, course and treatment of depression.

Keywords: AMPA receptors; Ampakines; Depression; Glutamatergic synapse; Ketamine; MDD; Neuroplasticity; PDZ domain; Psychiatric disorders; Synaptic plasticity.

Publication types

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

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use
  • Central Nervous System / drug effects
  • Central Nervous System / metabolism*
  • Depression / drug therapy
  • Depression / pathology*
  • Humans
  • Ketamine / therapeutic use
  • Neuronal Plasticity / drug effects
  • Receptors, AMPA / metabolism*


  • Antidepressive Agents
  • Receptors, AMPA
  • Ketamine