title: Activation of the mTOR signaling pathway in the antidepressant-like activity of the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082 in the FST in rats.
abstract: Clinical studies have demonstrated rapid and long-lasting antidepressant effects of ketamine in depressive patients. It has been proposed that these effects are related to changes in synaptogenesis in the mechanism involving mammalian target of rapamycin (mTOR) activation. Similar mechanisms have been proposed for a group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. We aimed to investigate whether other mGlu receptor ligands that produce antidepressant-like effects, namely, the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082, induce the activation of mTOR signaling in the prefrontal cortex (PFC) in rats. AMN082 administered 60 min before the test increased the levels of pmTOR and pp70S6K, and the mTORC1 antagonist rapamycin reversed AMN082-induced changes in the forced swim test (FST) in rats. Furthermore, AMN082 administered 23 h before the decapitation of the rats increased the levels of synapsin I and GluR1, although it did not produce any effect in the FST at the same time point. However, MTEP induced a rapid but unsustained antidepressant-like effect, which was not related to the activation of the mTOR cascade. Finally, the antidepressant-like effects of MTEP or AMN082 were not antagonized by NBQX. In summary, the antidepressant-like activity of MTEP did not depend on the activation of mTOR signaling. However, we observed a unique feature of the mechanism of AMN082. The drug stimulated the mTOR signaling pathway and synaptic protein levels (like ketamine), while it did not induce a sustained antidepressant effect and its action was not directly dependent on AMPA receptor activation (as in classic antidepressants (ADs)).
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Neurobiology, Smętna 12, 31-343 Kraków, Poland. Electronic address: nfpaluch@cyf-kr.edu.pl.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Pałucha-Poniewiera
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Neurobiology, Smętna 12, 31-343 Kraków, Poland.
authors.forename: Bernadeta
authors.initials: B
authors.lastname: Szewczyk
authors.affiliation: Institute of Pharmacology Polish Academy of Sciences, Department of Neurobiology, Smętna 12, 31-343 Kraków, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Pilc
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013550:Swimming; D016704:Synapsins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D001559:Benzhydryl Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011725:Pyridines; D011810:Quinoxalines; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D020123:Sirolimus; D016704:Synapsins; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; C578937:Grm5 protein, rat; C507346:N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride; C102719:metabotropic glutamate receptor 7; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C546845:mTOR protein, rat
keywords: AMN082; Antidepressant; MTEP; mGlu receptors; mTOR