mTOR activation is required for the antidepressant effects of mGluR2/3 blockade
Jason M. Dwyer, Ashley E. Lepack, Ronald S. Duman
The International Journal of Neuropsychopharmacology November 24, 2011 DOI: 10.1017/s1461145711001702 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | LY 341495 |
| Dose | single dose (exact dose not stated) |
| Duration | 1 hour and 24 hours post-administration |
| Measures | forced swim test |
| Topics | Ketamine |
| Keywords | Pi3k/akt/mtor pathway Antidepressant Synaptogenesis Pharmacology Prefrontal cortex Metabotropic glutamate receptor Behavioural despair test Synapsin i Antagonist Nmda receptor Blockade Hippocampus Signal transduction Cell biology Biochemistry |
| Citations | 169 |
| Key points | The antidepressant effects of LY 341495 in the rat forced swim test are completely blocked by the mTOR inhibitor rapamycin, indicating that its actions are mediated by mTOR activation. |
Abstract
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.