Contribution of NMDA, GABA_A and GABA_B receptors and l-arginine-NO-cGMP, MEK1/2 and CaMK-II pathways in the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in mice

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• 作者：Ana Paula Pesarico ; Eluza Curte Stangherlin ; Suzan Gonç ; alves Rosa ; Anderson C. Mantovani ; Gilson Zeni ; Cristina Wayne Nogueira ; ^{criswn@ufsm.br" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Depression ; Isoquinoline ; Glutamate ; GABA ; Nitric oxide ; MEK/CaMKII
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：5 July 2016
• 年：2016
• 卷：782
• 期：Complete
• 页码：6-13
• 全文大小：1240 K

文摘

It has been reported that the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) may result from the modulation of brain monoaminergic systems. However, the mechanisms of FDPI action are not fully understood. The aim of this study was to investigate the contribution of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid (GABA) systems as well as l-arginine-nitric oxide-(NO)-cyclic guanosine monophosphate-(cGMP), mitogen-activated protein/extracellular signal-regulated kinase (MEK1/2) and Ca²⁺/calmodulin-dependent protein kinase II (CaMK-II) signaling pathways in the antidepressant-like effect of FDPI in the mouse forced swimming test (FST). The levels of NO and uptake of [³H]glutamate and [³H]GABA were determined in prefrontal cortices of Swiss mice. Pretreatments with NMDA (0.1 pmol/site, i.c.v., a NMDA receptor agonist), bicuculline (1 mg/kg, i.p., a GABA_A receptor antagonist), phaclofen (2 mg/kg, i.p., a GABA_B receptor antagonist) and l-arginine (750 mg/kg, i.p., a NO precursor), KN-62 (1 μg/site, a CaMK-II inhibitor), U0126 (5 μg/site, a MEK1/2 inhibitor) and PD09058 (5 μg/site, a MEK1/2 inhibitor) blocked the antidepressant-like effect of FDPI, at a dose of 1 mg/kg, in the FST. ODQ (30 pmol/site, i.c.v., a soluble guanylate cyclase (sGC) inhibitor) in combination with a sub-effective dose of FDPI (0.1 mg/kg, i.g.) reduced the immobility time in the FST. The administration of FDPI (50 mg/kg) to mice increased the glutamate uptake and reduced NO levels in the prefrontal cortex of mice. The results suggest a contribution of NMDA, GABA_A and GABA_B receptors and l-arginine-NO-cGMP pathway in the antidepressant-like action of FDPI in mice, and this effect is related to CaMK-II and MEK 1/2 activation.