title: Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists.
abstract: Growing evidence has indicated that the blockade of group II metabotropic glutamate (mGlu2/3) receptor exerts antidepressant-like effects in several animal models of depression. However, the molecular mechanisms underlying the action of mGlu2/3 receptor antagonists are not well understood. Here, we investigated the involvement of mammalian target of rapamycin (mTOR) signaling in the acute and sustained antidepressant-like effects of mGlu2/3 receptor antagonists such as (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495). Mice were subjected to a tail suspension test (TST) to assess the acute and sustained antidepressant-like effects. We evaluated the effect of rapamycin, an mTOR antagonist, on the acute and sustained antidepressant-like effects of mGlu2/3 receptor antagonists. Both MGS0039 and LY341495 exerted antidepressant-like effects, as evaluated using the TST; these effects were sustained for 24 h. Pretreatment with rapamycin blocked the sustained, but not the acute, antidepressant-like effects of mGlu2/3 receptor antagonists, as observed in ketamine. The present result suggests that the blockade of the mGlu2/3 receptor may activate mTOR signaling, and that the activation of mTOR signaling may contribute to the sustained antidepressant-like effects of mGlu2/3 receptor antagonists.
authors: Discovery Pharmacology, Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
authors: Hiroyuki
authors: H
authors: Koike
authors: Michihiko
authors: M
authors: Iijima
authors: Shigeyuki
authors: S
authors: Chaki
mesh_terms: D000596:Amino Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy*; D003998:Dicarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019417:Hindlimb Suspension / Q000379:methods; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014966:Xanthenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C483757:2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo(3.1.0)hexane-2,6-dicarboxylic acid; D000596:Amino Acids; D001643:Bridged Bicyclo Compounds; D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; D007649:Ketamine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus