Contribution of NMDA, GABAA and GABAB 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.
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 Ca(2+)/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 [(3)H]glutamate and [(3)H]GABA were determined in prefrontal cortices of Swiss mice. Pretreatments with NMDA (0.1 pmol/site, i.c.v., a NMDA receptor agonist), bicuculline (1mg/kg, i.p., a GABAA receptor antagonist), phaclofen (2mg/kg, i.p., a GABAB receptor antagonist) and l-arginine (750mg/kg, i.p., a NO precursor), KN-62 (1μg/site, a CaMK-II inhibitor), U0126 (5μg/site, a MEK1/2 inhibitor) and PD09058 (5μg/site, a MEK1/2 inhibitor) blocked the antidepressant-like effect of FDPI, at a dose of 1mg/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 (0.1mg/kg, i.g.) reduced the immobility time in the FST. The administration of FDPI (50mg/kg) to mice increased the glutamate uptake and reduced NO levels in the prefrontal cortex of mice. The results suggest a contribution of NMDA, GABAA and GABAB 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.
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil.
Ana Paula
AP
Pesarico
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil.
Eluza Curte
EC
Stangherlin
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil.
Suzan Gonçalves
SG
Rosa
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil.
Anderson C
AC
Mantovani
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil.
Gilson
G
Zeni
Laboratório de Síntese, Reatividade e Avaliação Farmacológica e Toxicológica de Organocalcogênios, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, CEP 97105-900, Santa Maria, Rio Grande do Sul, Brazil. Electronic address: criswn@ufsm.br.
Cristina Wayne
CW
Nogueira
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001120:Arginine / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
C000614591:7-fluoro-1,3-diphenylisoquinoline-1-amine; D000928:Antidepressive Agents; D011804:Quinolines; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D016202:N-Methylaspartate; D001120:Arginine; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D006152:Cyclic GMP
Depression; GABA; Glutamate; Isoquinoline; MEK/CaMKII; Nitric oxide