title: 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.
authors: Yale University School of Medicine, New Haven, CT 06508, USA.
authors: Jason M
authors: JM
authors: Dwyer
authors: Ashley E
authors: AE
authors: Lepack
authors: Ronald S
authors: RS
authors: Duman
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013550:Swimming / Q000523:psychology; D016704:Synapsins / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; C114624:LY 341495; D008565:Membrane Proteins; D018094:Receptors, Metabotropic Glutamate; D016704:Synapsins; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C104077:metabotropic glutamate receptor type 1; D007649:Ketamine; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases