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

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.

Figures

Fig. 1

(a, b) LY341495 increases mTOR signaling in the PFC. Phosphorylation of 4E-BP1, mTOR, p70S6K and ERK is increased 1 hr after a single i.p. injection of LY341495 (3 and 10 mg/kg). Levels of phosphorylated proteins were normalized to either GAPDH (4E-BP1) or levels of total protein (p70S6K, mTOR, and ERK). (c, d) LY341495 increases synaptic protein expression in the PFC. PSD-95, GluR1 and Synapsin I expression is increased 24 hrs after a single i.p. injection of LY341495 (3 or 10 mg/kg) or ketamine (10 mg/kg). Levels of synaptic proteins were normalized to GAPDH. Results are expressed as fold change compared to vehicle control, and are the mean ± SEM (n=3–4, *P<0.05, **P<0.01 compared to vehicle; ANOVA)

Fig. 2

Rapamycin blocks the antidepressant effects of LY341495. Rats received an ICV infusion of rapamycin (0.2 nmol) 30 min before a single i.p. injection of LY341495 (3 mg/kg). 24 hrs after treatment, LY341495 significantly decreased immobility time and rapamycin pretreatment completely blocked this effect. Results are mean ± SEM (n=6–8, *P<0.05; ANOVA)