PMID- 28695335 OWN - NLM STAT- MEDLINE DCOM- 20180629 LR - 20211204 IS - 1435-1463 (Electronic) IS - 0300-9564 (Linking) VI - 124 IP - 10 DP - 2017 Oct TI - Glutamatergic system and mTOR-signaling pathway participate in the antidepressant-like effect of inosine in the tail suspension test. PG - 1227-1237 LID - 10.1007/s00702-017-1753-4 [doi] AB - Glutamatergic system and mTOR signaling pathway have been proposed to be important targets for pharmacological treatment of major depressive disorder. Previous studies have shown that inosine, an endogenous purine, is able to exert a remarkable antidepressant-like effect in mice. Nevertheless, the role of glutamatergic system and mTOR in this effect was not previously determined. This study was designed to investigate the possible modulation of NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mTOR complex 1 (mTORC1) signaling pathway in the inosine anti-immobility effect in the tail suspension test (TST) in mice. Pre-treatment of mice with NMDA (0.1 pmol/mouse, NMDAR agonist, i.c.v.) and D-serine (30 mug/mouse, NMDAR co-agonist, i.c.v.) prevented inosine (10 mg/kg, i.p.) anti-immobility effect in the TST. In addition, a synergistic antidepressant-like effect was observed when a sub-effective dose of inosine (0.1 mg/kg, i.p.) was combined with sub-effective doses of NMDAR antagonists MK-801 (0.001 mg/kg, p.o.) or ketamine (0.1 mg/kg, i.p.). Conversely, the antidepressant-like effect elicited by inosine was not altered by pre-treatment with AMPAR antagonist, DNQX (2.5 mug/mouse, i.c.v.). The mTORC1 inhibitor rapamycin (0.2 nmol/mouse, i.c.v.) prevented the inosine anti-immobility effect in the TST. Noteworthy, inosine treatment did not change the immunocontent of the synaptic proteins PSD95, GluA1 and synapsin I. Mice locomotor activity assessed by open-field test, was not altered by treatments. Taken together, this study shows a pivotal role of NMDAR inhibition and mTORC1 activation for inosine antidepressant-like effect and extends the knowledge concerning the molecular mechanism and potential of inosine for antidepressant strategies. FAU - Goncalves, Filipe Marques AU - Goncalves FM AD - Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Neis, Vivian Binder AU - Neis VB AD - Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Rieger, Debora Kurrle AU - Rieger DK AD - Department of Nutrition, Center of Health Science, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Peres, Tanara V AU - Peres TV AD - Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Lopes, Mark William AU - Lopes MW AD - Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Heinrich, Isabella A AU - Heinrich IA AD - Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Costa, Ana Paula AU - Costa AP AD - Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Rodrigues, Ana Lucia S AU - Rodrigues ALS AD - Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. AD - Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. AD - Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Kaster, Manuella P AU - Kaster MP AD - Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. AD - Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. FAU - Leal, Rodrigo Bainy AU - Leal RB AUID- ORCID: 0000-0003-2536-6888 AD - Biochemistry Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. rbleal@gmail.com. AD - Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. rbleal@gmail.com. AD - Neuroscience Graduate Program, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianopolis, Santa Catarina, 88040900, Brazil. rbleal@gmail.com. LA - eng GR - 308449/2016-9/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ GR - 308459/2013-0/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ GR - 308723/2013-9/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ GR - 481523/2013-8/Conselho Nacional de Desenvolvimento Cientifico e Tecnologico/ GR - PROESP/CAPES; #1509/2009/Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/ GR - CAPES/MINCyT; #249/14/Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior/ GR - FAPESC/PRONEX Program-NENASC Project; #1262/2012-9/Fundacao de Amparo a Pesquisa e Inovacao do Estado de Santa Catarina/ PT - Journal Article DEP - 20170710 PL - Austria TA - J Neural Transm (Vienna) JT - Journal of neural transmission (Vienna, Austria : 1996) JID - 9702341 RN - 0 (Antidepressive Agents) RN - 0 (Disks Large Homolog 4 Protein) RN - 0 (Dlg4 protein, mouse) RN - 0 (Excitatory Amino Acid Agents) RN - 0 (Receptors, AMPA) RN - 3KX376GY7L (Glutamic Acid) RN - 5A614L51CT (Inosine) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - TFZ3H25BS1 (glutamate receptor ionotropic, AMPA 1) SB - IM MH - Analysis of Variance MH - Animals MH - Antidepressive Agents/*therapeutic use MH - Depression/diagnosis/*drug therapy MH - Disease Models, Animal MH - Disks Large Homolog 4 Protein/metabolism MH - Dose-Response Relationship, Drug MH - Excitatory Amino Acid Agents/pharmacology MH - Exploratory Behavior/drug effects MH - Gene Expression Regulation/drug effects MH - Glutamic Acid/*metabolism MH - Hindlimb Suspension/methods MH - Inosine/*therapeutic use MH - Male MH - Mice MH - Receptors, AMPA/metabolism MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/*metabolism OTO - NOTNLM OT - Antidepressant OT - Glutamatergic system OT - Inosine OT - mTOR EDAT- 2017/07/12 06:00 MHDA- 2018/06/30 06:00 CRDT- 2017/07/12 06:00 PHST- 2017/02/17 00:00 [received] PHST- 2017/07/01 00:00 [accepted] PHST- 2017/07/12 06:00 [pubmed] PHST- 2018/06/30 06:00 [medline] PHST- 2017/07/12 06:00 [entrez] AID - 10.1007/s00702-017-1753-4 [pii] AID - 10.1007/s00702-017-1753-4 [doi] PST - ppublish SO - J Neural Transm (Vienna). 2017 Oct;124(10):1227-1237. doi: 10.1007/s00702-017-1753-4. Epub 2017 Jul 10.