The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN

Neuropsychopharmacology. 2016 Mar;41(4):1046-56. doi: 10.1038/npp.2015.233. Epub 2015 Aug 6.


We have reported the antidepressant effects of both metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and ketamine in several animal models, and proposed that serotonergic (5-HTergic) transmission is involved in these actions. Given that the projections from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN), where the majority of serotonin (5-HT) neurons exist, are reportedly involved in the antidepressant effects, in this study, we investigated using the forced swimming test (FST) of C57BL/6J male mice, the role of 5-HT neurons in the DRN regulated by the mPFC-DRN projections in the antidepressant effects of an mGlu2/3 receptor antagonist, LY341495, and ketamine. Following systemic administration/microinjection into the mPFC, both LY341495 and ketamine were found to exert antidepressant effects in the FST, and the effects were attenuated by depletion of 5-HT by treatment with an inhibitor of 5-HT synthesis, PCPA. The antidepressant effects of LY341495 and ketamine were also blocked by systemic administration/microinjection into the mPFC of an AMPA receptor antagonist, NBQX. Moreover, systemic administration/microinjection into the mPFC of LY341495 and ketamine significantly increased the c-Fos expression in the 5-HT neurons in the DRN, and the effect of systemic administration of these drugs on the neuronal c-Fos expression was attenuated by microinjection of NBQX into the mPFC. Our findings suggest that activation of 5-HT neurons in the DRN regulated by stimulation of the AMPA receptor in the mPFC may be involved in the antidepressant effects of an mGlu2/3 receptor antagonist and ketamine.

MeSH terms

  • Amino Acids / administration & dosage
  • Animals
  • Antidepressive Agents / administration & dosage*
  • Depression / prevention & control*
  • Dorsal Raphe Nucleus / drug effects
  • Dorsal Raphe Nucleus / physiology*
  • Fenclonine / administration & dosage
  • Ketamine / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / physiology*
  • Quinoxalines / administration & dosage
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / physiology*
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / physiology*
  • Xanthenes / administration & dosage


  • Amino Acids
  • Antidepressive Agents
  • LY 341495
  • Quinoxalines
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • Xanthenes
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Ketamine
  • Fenclonine