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Involvement of NO/cGMP pathway in the antidepressant-like effect of gabapentin in mouse forced swimming test

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Abstract

Based on clinical studies regarding the beneficial effect of gabapentin in depression, we aimed to evaluate the antidepressant-like properties of gabapentin in mice and also the participation of nitric oxide (NO)/cyclic guanosine monophosphate pathway in this effect. The following drugs were used in this study: gabapentin; N(G)-nitro-l-arginine methyl ester (L-NAME), a non-specific NO synthase (NOS) inhibitor; 7-nitroindazole, a specific neuronal NOS inhibitor; aminoguanidine, a specific inducible NOS inhibitor; l-arginine, a NO precursor; and sildenafil, a phosphodiestrase inhibitor. Finally, we studied the behavioral effects through the forced swimming test (FST) and the changes of the hippocampus NO level through nitrite assay. The immobility time was significantly reduced after gabapentin administration. Co-administration of non-effective doses of gabapentin and L-NAME or 7-nitroindazole (7-NI) resulted in antidepressant-like effect in FST, while aminoguanidine did not affect the immobility time of gabapentin-treated mice. Furthermore, the antidepressant-like property of gabapentin was prevented by l-arginine or sildenafil. Also, the hippocampal nitrite level was significantly lower in gabapentin-treated mice relative to saline-injected mice, and co-administration of 7-NI with sub-effective gabapentin caused a significant decrease in hippocampal nitrite levels. Our results indicate that the antidepressant-like effect of gabapentin in the mice FST model is mediated at least in part through nitric oxide/cyclic guanosine monophosphate (cGMP) pathway.

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References

  • Altshuler LL, Keck PE Jr, McElroy SL, Suppes T, Brown ES, Denicoff K, Frye M, Gitlin M, Hwang S, Goodman R (1999) Gabapentin in the acute treatment of refractory bipolar disorder. Bipolar Disord 1:61–65

    Article  CAS  PubMed  Google Scholar 

  • Astaneh AN, Rezaei O (2012) Adjunctive treatment with gabapentin in bipolar patients during acute mania. Int J Psychiat Med 43:261–271

    Article  Google Scholar 

  • Bang S, Yoo S, Hwang SW (2009) Gabapentin attenuates the activation of transient receptor potential A1 by cinnamaldehyde. Exp Neurobiol 18:1–7

    Article  Google Scholar 

  • Beavo JA (1995) Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 75:725–748

    CAS  PubMed  Google Scholar 

  • Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7:137–151

    Article  CAS  PubMed  Google Scholar 

  • Bortalanza LB, Ferreira J, Hess SC, Delle Monache F, Yunes RA, Calixto JB (2002) Anti-allodynic action of the tormentic acid, a triterpene isolated from plant, against neuropathic and inflammatory persistent pain in mice. Eur J Pharmacol 453:203–208

    Article  CAS  PubMed  Google Scholar 

  • Cheng J-K, Chiou L-C (2006) Mechanisms of the antinociceptive action of gabapentin. J Pharmacol Sci 100:471–486

    Article  CAS  PubMed  Google Scholar 

  • Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245

    Article  CAS  PubMed  Google Scholar 

  • Denninger JW, Marletta MA (1999) Guanylate cyclase and the < sup > ⋅</sup > NO/cGMP signaling pathway. BBABioenergetics 1411:334–350

    Article  CAS  Google Scholar 

  • Dhir A, Kulkarni S (2007) Involvement of l-arginine–nitric oxide–cyclic guanosine monophosphate pathway in the antidepressant-like effect of venlafaxine in mice. Prog Neuro-Psychoph 31:921–925

    Article  CAS  Google Scholar 

  • Domek-Lopacinska K, Strosznajder J (2005) Cyclic GMP metabolism and its role in brain physiology. J Physio Pharmacol 56:15

    Google Scholar 

  • Dubovsky S (1993) Calcium antagonists in manic-depressive illness. Neuropsychobiology 27:184–192

    Article  CAS  PubMed  Google Scholar 

  • Eckeli AL, Dach F, Rodrigues ALS (2000) Acute treatments with GMP produce antidepressant-like effects in mice. Neuroreport 11:1839–1843

  • Erfurth A, Kammerer C, Grunze H, Normann C, Walden J (1998) An open label study of gabapentin in the treatment of acute mania. J Psychiat Res 32:261–264

    Article  CAS  PubMed  Google Scholar 

  • Esplugues JV (2002) NO as a signalling molecule in the nervous system. Brit J Pharmacol 135:1079–1095

    Article  CAS  Google Scholar 

  • Frye MA, Ketter TA, Kimbrell TA, Dunn RT, Speer AM, Osuch EA, Luckenbaugh DA, Corá-Locatelli G, Leverich GS, Post RM (2000) A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharm 20:607–614

    Article  CAS  Google Scholar 

  • Furuta S, Shimizu T, Narita M, Matsumoto K, Kuzumaki N, Horie S, Suzuki T, Narita M (2009) Subdiaphragmatic vagotomy promotes nociceptive sensitivity of deep tissue in rats. Neuroscience 164(3):1252–1262

  • Garthwaite J, Boulton C (1995) Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57:683–706

    Article  CAS  PubMed  Google Scholar 

  • Ghaemi SN, Katzow JJ, Desai SP, Goodwin FK (1998) Gabapentin treatment of mood disorders: a preliminary study. J Clin Psychiat 59:426–429

    Article  CAS  Google Scholar 

  • Ghasemi M, Sadeghipour H, Mosleh A, Sadeghipour HR, Mani AR, Dehpour AR (2008) Nitric oxide involvement in the antidepressant-like effects of acute lithium administration in the mouse forced swimming test. Eur Neuropsychopharm 18:323–332

    Article  CAS  Google Scholar 

  • Goldlust A, Su T-Z, Welty DF, Taylor CP, Oxender DL (1995) Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. Epilepsy Res 22:1–11

    Article  CAS  PubMed  Google Scholar 

  • Granger DL, Taintor RR, Boockvar KS, Hibbs JB (1996) Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods Enzymol 268:142–151

    Article  CAS  PubMed  Google Scholar 

  • Gustafsson H, Flood K, Berge O-G, Brodin E, Olgart L, Stiller C-O (2003) Gabapentin reverses mechanical allodynia induced by sciatic nerve ischemia and formalin-induced nociception in mice. Expe Neurol 182:427–434

    Article  CAS  Google Scholar 

  • Haj-Mirzaian A, Ostadhadi S, Kordjazy N, Dehpour AR, Ejtemaei Mehr S (2014) Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test. Eur J Pharmacol 735:26–31

    Article  CAS  PubMed  Google Scholar 

  • Haj-Mirzaian A, Kordjazy N, Haj-Mirzaian A, Ostadhadi S, Ghasemi M, Amiri S, Faizi M, Dehpour A (2015) Evidence for the involvement of NMDA receptors in the antidepressant-like effect of nicotine in mouse forced swimming and tail suspension tests. Psychopharmacology 232:3551–3561

    Article  CAS  PubMed  Google Scholar 

  • Hara K, Sata T (2007) Inhibitory effect of gabapentin on N-methyl-d-aspartate receptors expressed in Xenopus oocytes. Acta Anaesth Scand 51:122–128

    Article  CAS  PubMed  Google Scholar 

  • Harvey BH, Oosthuizen F, Brand L, Wegener G, Stein DJ (2004) Stress–restress evokes sustained iNOS activity and altered GABA levels and NMDA receptors in rat hippocampus. Psychopharmacology 175:494–502

    Article  CAS  PubMed  Google Scholar 

  • Harkin A, Connor T, Walsh M, St John N, Kelly J (2003) Serotonergic mediation of the antidepressant-like effects of nitric oxide synthase inhibitors. Neuropharmacology 44:616–623

    Article  CAS  PubMed  Google Scholar 

  • Harkin A, Connor TJ, Burns MP, Kelly JP (2004) Nitric oxide synthase inhibitors augment the effects of serotonin re-uptake inhibitors in the forced swimming test. Eur Neuropsychopharm 14:274–281

    Article  CAS  Google Scholar 

  • Harkin AJ, Bruce KH, Craft B, Paul IA (1999) Nitric oxide synthase inhibitors have antidepressant-like properties in mice: 1. acute treatments are active in the forced swim test. Eur J Pharmacol 372:207–213

    Article  CAS  PubMed  Google Scholar 

  • Joca SRL, Guimarães FS (2006) Inhibition of neuronal nitric oxide synthase in the rat hippocampus induces antidepressant-like effects. Psychopharmacology 185:298–305

    Article  CAS  PubMed  Google Scholar 

  • Kaster MP, Rosa AO, Santos AR, Rodrigues ALS (2005) Involvement of nitric oxide–cGMP pathway in the antidepressant-like effects of adenosine in the forced swimming test. Int J Neuropsychopharm 8:601–606

    Article  CAS  Google Scholar 

  • Kessler RC, Merikangas KR, Wang PS (2007) Prevalence, comorbidity, and service utilization for mood disorders in the United States at the beginning of the twenty-first century. Annu Rev Clin Psychol 3:137–158

  • Khan MI, Ostadhadi S, Zolfaghari S, Mehr SE, Hassanzadeh G, Dehpour A-R (2016) The involvement of NMDA receptor/NO/cGMP pathway in the antidepressant like effects of baclofen in mouse force swimming test. Neurosci Lett 62:52–61

    Article  Google Scholar 

  • Knoll J, Stegman K, Suppes T (1998) Clinical experience using gabapentin adjunctively in patients with a history of mania or hypomania. J Affect Disorders 49:229–233

    Article  CAS  PubMed  Google Scholar 

  • Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals. Biochem J 298:249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kordjazy N, Haj-Mirzaian A, Amiri S, Ostadhadi S, Kordjazy M, Sharifzadeh M, Dehpour AR (2015) Elevated level of nitric oxide mediates the anti-depressant effect of rubidium chloride in mice. Eur J Pharmacol 762:411–418

    Article  CAS  PubMed  Google Scholar 

  • Kordjazy N, Haj-Mirzaian A, Amiri S, Ostadhadi S, Amini-khoei H, Dehpour AR (2016) Involvement of N-methyl-daspartate receptors in the antidepressant-like effect of 5-hydroxytryptamine 3 antagonists in mouse forced swimming test and tail suspension test. Pharmacol Biochem Be 141:1–9

    Article  CAS  Google Scholar 

  • Marais E, Klugbauer N, Hofmann F (2001) Calcium channel α2δ subunits—structure and gabapentin binding. Mol Pharmacol 59:1243–1248

    CAS  PubMed  Google Scholar 

  • McElroy SL, Soutullo CA, Keck PE Jr, Kmetz GF (1997) A pilot trial of adjunctive gabapentin in the treatment of bipolar disorder. Ann Clin Psychiatry 9:99–103

    Article  CAS  PubMed  Google Scholar 

  • McLeod T, Lopez-Figueroa A, Lopez-Figueroa M (2000) Nitric oxide, stress, and depression. Psychopharmacol Bull 35:24–41

    Google Scholar 

  • Miranda HF, Sierralta F, Lux S, Troncoso R, Ciudad N, Zepeda R, Zanetta P, Noriega V, Prieto JC (2015) Involvement of nitridergic and opioidergic pathways in the antinociception of gabapentin in the orofacial formalin test in mice. Pharmacol Rep 67:399–403

    Article  CAS  PubMed  Google Scholar 

  • Nanri K, Montécot C, Springhetti V, Seylaz J, Pinard E (1998) The selective inhibitor of neuronal nitric oxide synthase, 7-nitroindazole, reduces the delayed neuronal damage due to forebrain ischemia in rats. Stroke 29:1248–1254

    Article  CAS  PubMed  Google Scholar 

  • Nemeroff CB, Owens MJ (2002) Treatment of mood disorders. Nat Neurosci 5:1068–1070

    Article  CAS  PubMed  Google Scholar 

  • Oka M, Itoh Y, Wada M, Yamamoto A, Fujita T (2003) Gabapentin blocks L-type and P/Q-type Ca2+ channels involved in depolarization-stimulated nitric oxide synthase activity in primary cultures of neurons from mouse cerebral cortex. Pharmaceut Res 20:897–899

    Article  CAS  Google Scholar 

  • Ostadhadi S, Haj-Mirzaian A, Nikoui V, Kordjazy N, Dehpour AR (2015) Involvement of opioid system in antidepressant-like effect of the cannabinoid CB1 receptor inverse agonist AM-251 after physical stress in mice. Clin Exp Pharmacol P. doi:10.1111/1440-1681.12518

    Google Scholar 

  • Pande AC, Davidson JR, Jefferson JW, Janney CA, Katzelnick DJ, Weisler RH, Greist JH, Sutherland SM (1999) Treatment of social phobia with gabapentin: a placebo-controlled study. J Clini Psychopharm 19:341–348

    Article  CAS  Google Scholar 

  • Pande AC, Pollack MH, Crockatt J, Greiner M, Chouinard G, Lydiard RB, Taylor CB, Dager SR, Shiovitz T (2000) Placebo-controlled study of gabapentin treatment of panic disorder. J Clini Psychopharm 20:467–471

    Article  CAS  Google Scholar 

  • Porsolt R, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacod T 229:327–336

    CAS  Google Scholar 

  • Rajasekaran K, Jayakumar R, Venkatachalam K (2003) Increased neuronal nitric oxide synthase (nNOS) activity triggers picrotoxin-induced seizures in rats and evidence for participation of nNOS mechanism in the action of antiepileptic drugs. Brain Res 979:85–97

    Article  CAS  PubMed  Google Scholar 

  • Rao ML, Clarenbach P, Vahlensieck M, Krätzschmar S (1988) Gabapentin augments whole blood serotonin in healthy young men. J Neural Transm 73:129–134

    Article  CAS  PubMed  Google Scholar 

  • Schulz R, Drayer RA, Rollman BL (2002) Depression as a risk factor for non-suicide mortality in the elderly. Biol Psychiatry 52:205–225

    Article  PubMed  Google Scholar 

  • Singh L, Field M, Ferris P, Hunter J, Oles R, Williams R, Woodruff G (1996) The antiepileptic agent gabapentin (Neurontin) possesses anxiolytic-like and antinociceptive actions that are reversed byd-serine. Psychopharmacology 127:1–9

    Article  CAS  PubMed  Google Scholar 

  • Southam E, Garthwaite J (1993) The nitric oxide-cyclic GMP signalling pathway in rat brain. Neuropharmacology 32:1267–1277

    Article  CAS  PubMed  Google Scholar 

  • Spiacci A Jr, Kanamaru F, Guimaraes F (2008) Nitric oxide-mediated anxiolytic-like and antidepressant-like effects in animal models of anxiety and depression. Pharmacol Biochem Behav 88:247–255

    Article  CAS  PubMed  Google Scholar 

  • Stanton S, Keck P Jr, McElroy S (1997) Treatment of acute mania with gabapentin. Am J Psychiatry 154:287

    CAS  PubMed  Google Scholar 

  • Stefani A, Spadoni F, Bernardi G (1998) Gabapentin inhibits calcium currents in isolated rat brain neurons. Neuropharmacology 37:83–91

    Article  CAS  PubMed  Google Scholar 

  • Stefani A, Spadoni F, Giacomini P, Lavaroni F, Bernardi G (2001) The effects of gabapentin on different ligand-and voltage-gated currents in isolated cortical neurons. Epilepsy Res 43:239–248

    Article  CAS  PubMed  Google Scholar 

  • Suman-Chauhan N, Webdale L, Hill DR, Woodruff GN (1993) Characterisation of [3H]gabapentin binding to a novel site in rat brain: homogenate binding studies. Europ J Pharmacol: Molec Pharmacol 244:293–301

    Article  CAS  Google Scholar 

  • Sutton K, Martin D, Pinnock R, Lee K, Scott R (2002) Gabapentin inhibits high‐threshold calcium channel currents in cultured rat dorsal root ganglion neurones. Br J Pharmacol 135:257–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taylor CP (1996) Mechanisms of action of gabapentin. Rev Neurol 153:S39–45

  • Vieta E, Martinez-Aran A, Nieto E, Colom F, Reinares M, Benabarre A, Gasto C (2000) Adjunctive gabapentin treatment of bipolar disorder. Europ Psychiatr 15:433–437

    Article  CAS  Google Scholar 

  • Volke V, Wegener G, Bourin M, Vasar E (2003) Antidepressant-and anxiolytic-like effects of selective neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole in mice. Behav Brain Res 140:141–147

    Article  CAS  PubMed  Google Scholar 

  • Wang PW, Santosa C, Schumacher M, Winsberg ME, Strong C, Ketter TA (2002) Gabapentin augmentation therapy in bipolar depression. Bipolar Disord 4:296–301

    Article  CAS  PubMed  Google Scholar 

  • Yasmin S, Carpenter LL, Leon Z, Siniscalchi JM, Price LH (2001) Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review. J Affect Disord 63:243–247

    Article  CAS  PubMed  Google Scholar 

  • Yildiz F, Erden BF, Ulak G, Utkan T, Gacar N (2000) Antidepressant-like effect of 7-nitroindazole in the forced swimming test in rats. Psychopharmacology 149:41–44

    Article  CAS  PubMed  Google Scholar 

  • Zomkowski AD, Engel D, Gabilan NH, Rodrigues ALS (2010) Involvement of NMDA receptors and l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effects of escitalopram in the forced swimming test. Eur Neuropsychopharmacol 20:793–801

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors are thankful to Mr. E Piryousefi for his helps in performing the experiments.

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Correspondence to AhmadReza Dehpour.

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Ostadhadi, S., Kordjazy, N., Haj-Mirzaian, A. et al. Involvement of NO/cGMP pathway in the antidepressant-like effect of gabapentin in mouse forced swimming test. Naunyn-Schmiedeberg's Arch Pharmacol 389, 393–402 (2016). https://doi.org/10.1007/s00210-015-1203-5

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