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The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test.
Pharmacol Biochem Behav. 2012 Dec; 103(2):408-17.PB

Abstract

Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor used as antidepressant. However, its mechanisms of action are not fully understood. This study investigated the effect of duloxetine in the mouse forced swimming test (FST) and in the tail suspension test (TST) and the involvement of the NMDA receptors and the l-arginine-NO-cGMP pathway in its effect in the FST. Duloxetine reduced the immobility time both in the FST and in the TST (dose range of 1-30mg/kg, i.p.), without changing locomotion in an open-field. Duloxetine administered orally (1-30mg/kg) also reduced the immobility time in the FST. The effect of duloxetine (10mg/kg, p.o.) in the FST was prevented by pre-treatment with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v.), (l-arginine (750mg/kg, i.p.), S-nitroso-N-acetyl-penicillamine (SNAP, 25μg/site, i.c.v) or sildenafil (5mg/kg, i.p.). The administration of MK-801 (0.001mg/kg, i.p.), 7-nitroindazole (50mg/kg, i.p.), methylene blue (20mg/kg, i.p.) or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (30pmol/site i.c.v.) in combination with a sub-effective dose of duloxetine (0.3mg/kg, p.o.) reduced the immobility time in the FST. Moreover, the administration of duloxetine (10mg/kg) produced a reduction in NOx levels in the hippocampus and cerebral cortex. Altogether the results suggest that the effect of duloxetine in the FST is dependent on either a blockade of NMDA receptors or an inhibition of NO. In addition, our results further reinforce the role of NMDA receptors and l-arginine-NO-cGMP pathway, besides the monoaminergic systems, in the mechanism of action of current prescribed antidepressant agents.

Authors+Show Affiliations

Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23010381

Citation

Zomkowski, Andréa D E., et al. "The Role of the NMDA Receptors and L-arginine-nitric Oxide-cyclic Guanosine Monophosphate Pathway in the Antidepressant-like Effect of Duloxetine in the Forced Swimming Test." Pharmacology, Biochemistry, and Behavior, vol. 103, no. 2, 2012, pp. 408-17.
Zomkowski AD, Engel D, Cunha MP, et al. The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test. Pharmacol Biochem Behav. 2012;103(2):408-17.
Zomkowski, A. D., Engel, D., Cunha, M. P., Gabilan, N. H., & Rodrigues, A. L. (2012). The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test. Pharmacology, Biochemistry, and Behavior, 103(2), 408-17. https://doi.org/10.1016/j.pbb.2012.09.011
Zomkowski AD, et al. The Role of the NMDA Receptors and L-arginine-nitric Oxide-cyclic Guanosine Monophosphate Pathway in the Antidepressant-like Effect of Duloxetine in the Forced Swimming Test. Pharmacol Biochem Behav. 2012;103(2):408-17. PubMed PMID: 23010381.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The role of the NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of duloxetine in the forced swimming test. AU - Zomkowski,Andréa D E, AU - Engel,Daiane, AU - Cunha,Mauricio P, AU - Gabilan,Nelson H, AU - Rodrigues,Ana Lúcia S, Y1 - 2012/09/23/ PY - 2011/12/22/received PY - 2012/09/10/revised PY - 2012/09/16/accepted PY - 2012/9/27/entrez PY - 2012/9/27/pubmed PY - 2013/6/12/medline SP - 408 EP - 17 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol. Biochem. Behav. VL - 103 IS - 2 N2 - Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor used as antidepressant. However, its mechanisms of action are not fully understood. This study investigated the effect of duloxetine in the mouse forced swimming test (FST) and in the tail suspension test (TST) and the involvement of the NMDA receptors and the l-arginine-NO-cGMP pathway in its effect in the FST. Duloxetine reduced the immobility time both in the FST and in the TST (dose range of 1-30mg/kg, i.p.), without changing locomotion in an open-field. Duloxetine administered orally (1-30mg/kg) also reduced the immobility time in the FST. The effect of duloxetine (10mg/kg, p.o.) in the FST was prevented by pre-treatment with NMDA (0.1pmol/site, i.c.v.), d-serine (30μg/site, i.c.v.), (l-arginine (750mg/kg, i.p.), S-nitroso-N-acetyl-penicillamine (SNAP, 25μg/site, i.c.v) or sildenafil (5mg/kg, i.p.). The administration of MK-801 (0.001mg/kg, i.p.), 7-nitroindazole (50mg/kg, i.p.), methylene blue (20mg/kg, i.p.) or 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ) (30pmol/site i.c.v.) in combination with a sub-effective dose of duloxetine (0.3mg/kg, p.o.) reduced the immobility time in the FST. Moreover, the administration of duloxetine (10mg/kg) produced a reduction in NOx levels in the hippocampus and cerebral cortex. Altogether the results suggest that the effect of duloxetine in the FST is dependent on either a blockade of NMDA receptors or an inhibition of NO. In addition, our results further reinforce the role of NMDA receptors and l-arginine-NO-cGMP pathway, besides the monoaminergic systems, in the mechanism of action of current prescribed antidepressant agents. SN - 1873-5177 UR - https://www.unboundmedicine.com/medline/citation/23010381/The_role_of_the_NMDA_receptors_and_l_arginine_nitric_oxide_cyclic_guanosine_monophosphate_pathway_in_the_antidepressant_like_effect_of_duloxetine_in_the_forced_swimming_test_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-3057(12)00269-9 DB - PRIME DP - Unbound Medicine ER -