mTOR activation is required for the antidepressant effects of mGluR2/3 blockade

A single dose of LY 341495, an mGluR₂/₃ antagonist, rapidly activates the mTOR pathway and increases synaptic proteins in the prefrontal cortex, similar to the fast-acting antidepressant ketamine. Within one hour, LY 341495 activates mTOR, p70S6K, and 4E-BP1, and 24 hours later elevates levels of PSD-95, GluR1, and Synapsin I. The antidepressant effects of LY 341495 in the rat forced swim test are completely blocked by the mTOR inhibitor rapamycin, indicating that these actions are mediated by mTOR activation. This suggests mGluR₂/₃ antagonists could produce rapid antidepressant effects in depressed patients.

Study at a glance

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.