Involvement of the mammalian target of rapamycin signaling in the antidepressant-like effect of group II metabotropic glutamate receptor antagonists

• Published in: Neuropharmacology 2011-12, Vol.61 (8), p.1419-1423
• Main Authors: Koike, Hiroyuki, Iijima, Michihiko, Chaki, Shigeyuki
• Format: Article
• Language: English
• Subjects: Amino Acids - pharmacology; Amino Acids - therapeutic use; Analysis of Variance; Animals; Antidepressant; Bridged Bicyclo Compounds - pharmacology; Bridged Bicyclo Compounds - therapeutic use; Depression; Depression - drug therapy; Dicarboxylic Acids - pharmacology; Dicarboxylic Acids - therapeutic use; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists - pharmacology; Hindlimb Suspension - methods; Ketamine - pharmacology; LY341495; Male; mGlu2/3 receptor; MGS0039; Mice; Mice, Inbred ICR; mTOR; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Sirolimus - pharmacology; Time Factors; TOR Serine-Threonine Kinases - metabolism; Xanthenes - pharmacology; Xanthenes - therapeutic use
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.08.034

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. ► mGlu2/3 receptor antagonists exerted sustained antidepressant effect, lasting for 24 h. ► Antidepressant effects of mGlu2/3 receptor antagonists was attenuated by rapamycin. ► mGlu2/3 receptor antagonists, like ketamine, may exert antidepressant effects via activation of mTOR signaling.