title: Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling.
abstract: The activation of AMPA receptors and mTOR signaling has been reported as mechanisms underlying the antidepressant effects of fast-acting agents, specially the NMDA receptor antagonist ketamine. In the present study, oral administration of agmatine (0.1mg/kg), a neuromodulator that has been reported to modulate NMDA receptors, caused a significant reduction in the immobility time of mice submitted to the tail suspension test (TST), an effect prevented by the administration of DNQX (AMPA receptor antagonist, 2.5μg/site, i.c.v.), BDNF antibody (1μg/site, i.c.v.), K-252a (TrkB receptor antagonist, 1μg/site, i.c.v.), LY294002 (PI3K inhibitor, 10nmol/site, i.c.v.) or rapamycin (selective mTOR inhibitor, 0.2nmol/site, i.c.v.). Moreover, the administration of lithium chloride (non-selective GSK-3β inhibitor, 10mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, 0.01μg/site, i.c.v.) in combination with a sub-effective dose of agmatine (0.0001mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. Furthermore, increased immunocontents of BDNF, PSD-95 and GluA1 were found in the prefrontal cortex of mice just 1h after agmatine administration. These results indicate that the antidepressant-like effect of agmatine in the TST may be dependent on the activation of AMPA and TrkB receptors, PI3K and mTOR signaling as well as inhibition of GSK-3β, and increase in synaptic proteins. The results contribute to elucidate the complex signaling pathways involved in the antidepressant effect of agmatine and reinforce the pivotal role of these molecular targets for antidepressant responses.
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Vivian Binder
authors.initials: VB
authors.lastname: Neis
authors.affiliation: Post-Graduate Nutrition Program, Center of Health Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Morgana
authors.initials: M
authors.lastname: Moretti
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Luis Eduardo B
authors.initials: LE
authors.lastname: Bettio
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Camille M
authors.initials: CM
authors.lastname: Ribeiro
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Priscila Batista
authors.initials: PB
authors.lastname: Rosa
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Filipe Marques
authors.initials: FM
authors.lastname: Gonçalves
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Mark William
authors.initials: MW
authors.lastname: Lopes
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil.
authors.forename: Rodrigo Bainy
authors.initials: RB
authors.lastname: Leal
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900 Florianópolis, SC, Brazil. Electronic address: alsrodri@gmail.com.
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
mesh_terms: D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D019417:Hindlimb Suspension; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D018091:Receptors, AMPA / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D018091:Receptors, AMPA; C056723:FG 9041; D000376:Agmatine; C546843:mTOR protein, mouse; D020813:Receptor, trkB; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3
keywords: AMPA; Agmatine; Antidepressant; BDNF; Tail suspension test; mTOR signaling