MTOR activation is required for the antidepressant effects of mGluR 2/3 blockade

Jason M. Dwyer, Ashley E. Lepack, Ronald S. Duman

Research output: Contribution to journalArticlepeer-review

151 Scopus citations


Recent studies demonstrate that ketamine, a fast-acting antidepressant, rapidly activates the mammalian target of rapamycin (mTOR) and increases synaptogenesis in the prefrontal cortex. Because of the side-effect and abuse potential of ketamine we are investigating alternative agents that produce similar effects. Here, we demonstrate that a single dose of LY 341495, an mGluR2/3 antagonist, produces ketamine-like biochemical and behavioural actions. LY 341495 administration rapidly (1 h) activates the mTOR pathway (mTOR, p70S6K, 4E-BP1) and subsequently (24 h later) increases levels of synaptic proteins (PSD-95, GluR1 and Synapsin I), similar to the effects of ketamine. Finally, the antidepressant effects of LY 341495 in the rat forced swim test are completely blocked by the mTOR inhibitor, rapamycin. The results indicate that the antidepressant actions of LY 341495 are mediated by activation of mTOR and suggest that this and other mGluR2/3 antagonists could produce rapid antidepressant effects in depressed patients.

Original languageEnglish
Pages (from-to)429-434
Number of pages6
JournalInternational Journal of Neuropsychopharmacology
Issue number4
StatePublished - May 2012
Externally publishedYes


  • Behaviour
  • depression
  • glutamate
  • ketamine
  • synapse


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