Abstract
Rationale
Previously, we showed that pioglitazone exerts its antidepressant-like effect through peroxisome proliferator-activated receptor gamma receptors and demonstrated the possible involvement of calcium-dependent nitric oxide synthase inhibitors. Based upon the in vitro results, pioglitazone reduces N-methyl-d-aspartate (NMDA)-mediated calcium currents in hippocampal neurons.
Objective
In this study, we evaluated the involvement of the NMDA receptor (NMDAR) on the antidepressant-like effect of pioglitazone in the forced swimming test (FST) in mice.
Method
After the assessment of locomotor activity in the open-field test, mice were forced to swim individually and the immobility time of the last 4 min was evaluated. Pioglitazone was administered orally with doses of 5, 10, and 20 mg/kg 4 h before FST. To assess the involvement of NMDARs in the possible antidepressant-like effect of pioglitazone, a selective glutamate receptor agonist, NMDA (75 mg/kg, intraperitoneally [i.p.] or 20 ng/mouse, intracerebroventricularly [i.c.v.]), was administered before pioglitazone (20 mg/kg). To further determine a possible role of NMDARs in this effect, a noncompetitive antagonist of the NMDA, MK-801 (0.05 mg/kg, i.p. or 100 ng/mouse, i.c.v.), was coadministered with pioglitazone (10 mg/kg) 4 h prior to FST.
Results
Pioglitazone (20 mg/kg) administered 4 h prior to FST significantly reduced the immobility time. Coadministration of the noneffective doses of pioglitazone and MK-801 revealed an antidepressant-like effect in FST. Moreover, NMDA significantly reversed the antidepressant-like effect of pioglitazone administered 4 h prior to FST.
Conclusion
The antidepressant-like effect of pioglitazone in the FST is mediated partly through NMDAR signaling. This study provides a new approach for the treatment of depression.
Similar content being viewed by others
References
Aihara M, Ida I, Yuuki N, Oshima A, Kumano H, Takahashi K, Fukuda M, Oriuchi N, Endo K, Matsuda H (2007) HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions. Psychiatry Res Neuroimaging 155:245–256
Allahtavakoli M, Shabanzadeh A, Roohbakhsh A, Pourshanazari A (2007) Combination therapy of rosiglitazone, a peroxisome proliferator activated receptor ligand, and NMDA receptor antagonist (MK 801) on experimental embolic stroke in rats. Basic Clin Pharmacol Toxicol 101:309–314
Anderson RJ, Freedland KE, Clouse RE, Lustman PJ (2001) The prevalence of comorbid depression in adults with diabetes. Diabetes Care 24:1069
Aoun P, Simpkins JW, Agarwal N (2003) Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells. Investig Ophthalmol Vis Sci 44:2999
Arroll B, Macgillivray S, Ogston S, Reid I, Sullivan F, Williams B, Crombie I (2005) Efficacy and tolerability of tricyclic antidepressants and SSRIs compared with placebo for treatment of depression in primary care: a meta-analysis. Ann Fam Med 3:449–456
Baxter AJ, Charlson FJ, Somerville AJ, Whiteford HA (2011) Mental disorders as risk factors: assessing the evidence for the global burden of disease study. BMC Med 9:134
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354
Bordet R, Ouk T, Petrault O, Gele P, Gautier S, Laprais M, Deplanque D, Duriez P, Staels B, Fruchart JC, Bastide M (2006) PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem Soc Trans 34:1341–1346
Brasier AR (2006) The NF-kappaB regulatory network. Cardiovasc Toxicol 6:111–130
Brocardo PS, Budni J, Lobato KR, Santos ARS, Rodrigues ALS (2009) Evidence for the involvement of the opioid system in the antidepressant-like effect of folic acid in the mouse forced swimming test. Behav Brain Res 200:122–127
Budni J, Lobato KR, Binfare RW, Freitas AE, Costa AP, Saavedra MD, Leal RB, Lopez MG, Rodrigues AL (2011) Involvement of PI3K, GSK-3beta and PPARgamma in the antidepressant-like effect of folic acid in the forced swimming test in mice. J Psychopharmacol. doi:10.1177/0269881111424456
Cho SI, Park UJ, Chung JM, Gwag BJ (2010) Neu 2000, an NR2B-selective, moderate NMDA receptor antagonist and potent spin trapping molecule for stroke. Drug News Perspect 23:549–556
Cimini A, Benedetti E, Cristiano L, Sebastiani P, D'amico M, D'angelo B, Di Loreto S (2005) Expression of peroxisome proliferator-activated receptors (PPARs) and retinoic acid receptors (RXRs) in rat cortical neurons. Neuroscience 130:325–337
Consoni FT, Vital MABF, Andreatini R (2006) Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test. Eur Neuropsychopharmacol 16:451–458
Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245
De Groot M, Anderson R, Freedland KE, Clouse RE, Lustman PJ (2001) Association of depression and diabetes complications: a meta-analysis. Psychosom Med 63:619
Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88:494–501
Eissa Ahmed AA, Al-Rasheed NM (2009) Antidepressant-like effects of rosiglitazone, a PPARgamma agonist, in the rat forced swim and mouse tail suspension tests. Behav Pharmacol 20:635–642
Esplugues JV (2002) NO as a signalling molecule in the nervous system. Br J Pharmacol 135:1079–1095
Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT (2002) Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol 51:694–702
Gardoni F, Ghiglieri V, Luca M, Calabresi P (2010) Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson's disease. Prog Brain Res 183:169–182
Geldmacher DS, Fritsch T, McClendon MJ, Landreth G (2011) A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol 68:45–50
Ghasemi M, Montaser-Kouhsari L, Shafaroodi H, Nezami BG, Ebrahimi F, Dehpour AR (2009) NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test. Psychopharmacology (Berl) 206:325–333
Ghasemi M, Raza M, Dehpour AR (2010) NMDA receptor antagonists augment antidepressant-like effects of lithium in the mouse forced swimming test. J Psychopharmacol 24:585–594
Gonzalez O, Berry J, McKnight-Eily L, Strine T, Edwards V, Lu H, Croft J (2010) Current depression among adults: United States, 2006 and 2008. Morb Mortal Wkly Rev 59:1229–1235
Hara MR, Snyder SH (2007) Cell signaling and neuronal death. Annu Rev Pharmacol Toxicol 47:117–141
Ibrahim L, Diazgranados N, Luckenbaugh DA, Machado-Vieira R, Baumann J, Mallinger AG, Zarate CA Jr (2011) Rapid decrease in depressive symptoms with an N-methyl-d-aspartate antagonist in ECT-resistant major depression. Prog Neuropsychopharmacol Biol Psychiatry 35:1155–1159
Ji-Rong Y, Bi-Rong D, Chang-Quan H, Zhen-Chan L, Hong-Mei W, Yan-Ling Z, Mattis TA (2009) Pro12Ala polymorphism in PPAR [gamma] 2 associated with depression in Chinese nonagenarians/centenarians. Arch Med Res 40:411–415
Kantrowitz JT, Javitt DC (2010) Thinking glutamatergically: changing concepts of schizophrenia based upon changing neurochemical models. Clin Schizophr Relat Psychoses 4:189–200
Katon W, Fan MY, Unützer J, Taylor J, Pincus H, Schoenbaum M (2008) Depression and diabetes: a potentially lethal combination. J Gen Intern Med 23:1571–1575
Kemp DE, Ismail-Beigi F, Calabrese JR (2009) Antidepressant response associated with pioglitazone: support for an overlapping pathophysiology between major depression and metabolic syndrome. Am J Psychiatry 166:619
Kemp DE, Ismail-Beigi F, Ganocy SJ, Conroy C, Gao K, Obral S, Fein E, Findling RL, Calabrese JR (2011) Use of insulin sensitizers for the treatment of major depressive disorder: a pilot study of pioglitazone for major depression accompanied by abdominal obesity. J Affect Disord 136:1164–1173
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
Kiaei M, Kipiani K, Chen J, Calingasan NY, Beal MF (2005) Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 191:331–336
Konarski JZ, McIntyre RS, Kennedy SH, Rafi Tari S, Soczynska JK, Ketter TA (2008) Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disord 10:1–37
Kummer MP, Heneka MT (2008) PPARs in Alzheimer’s disease. PPAR Res 2008:403896
Laursen SE, Belknap JK (1986) Intracerebroventricular injections in mice. Some methodological refinements. J Pharmacol Methods 16:355–357
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270:12953–12956
Mantovani M, Pertile R, Calixto JB, Santos AR, Rodrigues AL (2003) Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evidence for involvement of N-methyl-d-aspartate receptors and the l-arginine–nitric oxide pathway. Neurosci Lett 343:1–4
Metzler M (2011) Mutations in NMDA receptors influence neurodevelopmental disorders causing epilepsy and intellectual disability. Clin Genet 79:219–220
Milnerwood AJ, Raymond LA (2010) Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease. Trends Neurosci 33:513–523
Molina-Hernandez M, Tellez-Alcantara NP, Perez-Garcia J, Olivera-Lopez JI, Jaramillo-Jaimes MT (2008) Antidepressant-like actions of minocycline combined with several glutamate antagonists. Prog Neuropsychopharmacol Biol Psychiatry 32:380–386
Moncada S, Palmer R, Higgs E (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142
Munhoz CD, Garcia-Bueno B, Madrigal JL, Lepsch LB, Scavone C, Leza JC (2008) Stress-induced neuroinflammation: mechanisms and new pharmacological targets. Braz J Med Biol Res 41:1037–1046
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B (2008) Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Update regarding the thiazolidinediones. Diabetologia 51:8–11
Paul IA, Skolnick P (2003) Glutamate and depression: clinical and preclinical studies. Ann N Y Acad Sci 1003:250–272
Pancani T, Phelps JT, Searcy JL, Kilgore MW, Chen KC, Porter NM, Thibault O (2009) Distinct modulation of voltage-gated and ligand-gated Ca2+ currents by PPAR-gamma agonists in cultured hippocampal neurons. J Neurochem 109:1800–1811
Pereira MP, Hurtado O, Cardenas A, Bosca L, Castillo J, Davalos A, Vivancos J, Serena J, Lorenzo P, Lizasoain I, Moro MA (2006) Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 cause potent neuroprotection after experimental stroke through noncompletely overlapping mechanisms. J Cereb Blood Flow Metab 26:218–229
Poleszak E, Wlaz P, Kedzierska E, Nieoczym D, Wrobel A, Fidecka S, Pilc A, Nowak G (2007) NMDA/glutamate mechanism of antidepressant-like action of magnesium in forced swim test in mice. Pharmacol Biochem Behav 88:158–164
Porsolt RD, Bertin A, Jalfre M (1977) Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 229:327–336
Racke MK, Gocke AR, Muir M, Diab A, Drew PD, Lovett-Racke AE (2006) Nuclear receptors and autoimmune disease: the potential of PPAR agonists to treat multiple sclerosis. J Nutr 136:700–703
Riederer P, Bartl J, Laux G, Grünblatt E (2011) Diabetes type II: a risk factor for depression–Parkinson–Alzheimer? Neurotox Res 19:253–265
Rosa AO, Lin J, Calixto JB, Santos ARS, Rodrigues ALS (2003) Involvement of NMDA receptors and l-arginine–nitric oxide pathway in the antidepressant-like effects of zinc in mice. Behav Brain Res 144:87–93
Rosa AO, Kaster MP, Binfare RW, Morales S, Martin-Aparicio E, Navarro-Rico ML, Martinez A, Medina M, Garcia AG, Lopez MG, Rodrigues AL (2008) Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice. Prog Neuropsychopharmacol Biol Psychiatry 32:1549–1556
Sadaghiani MS, Javadi-Paydar M, Gharedaghi MH, Fard YY, Dehpour AR (2011) Antidepressant-like effect of pioglitazone in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway. Behav Brain Res 224:336–343
Schintu N, Frau L, Ibba M, Caboni P, Garau A, Carboni E, Carta AR (2009) PPAR gamma mediated neuroprotection in a chronic mouse model of Parkinson’s disease. Eur J Neurosci 29:954–963
Schutz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE, Schurmann B, Zimmer A, Heneka MT (2005) The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci 25:7805–7812
Skolnick P, Popik P, Trullas R (2009) Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci 30:563–569
Tokita K, Yamaji T, Hashimoto K (2011) Roles of glutamate signaling in preclinical and/or mechanistic models of depression. Pharmacol Biochem Behav
Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185:1–10
Wilken R, Veena MS, Wang MB, Srivatsan ES (2011) Curcumin: a review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer 10:12
Yaffe K, Kanaya A, Lindquist K, Hsueh W, Cummings S, Beamer B, Newman A, Rosano C, Li R, Harris T (2008) PPAR-[gamma] Pro12Ala genotype and risk of cognitive decline in elders. Neurobiol Aging 29:78–83
Yki-Järvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106–1118
Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856–864
Zekry D, Gold G (2010) Management of mixed dementia. Drugs Aging 27:715–728
Zhang F, Sowers JR, Ram JL, Standley PR, Peuler JD (1994) Effects of pioglitazone on calcium channels in vascular smooth muscle. Hypertension 24:170–175
Zhao X, Ou Z, Grotta JC, Waxham N, Aronowski J (2006) Peroxisome-proliferator-activated receptor-gamma (PPAR [gamma]) activation protects neurons from NMDA excitotoxicity. Brain Res 1073:460–469
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Salehi-Sadaghiani, M., Javadi-Paydar, M., Gharedaghi, M.H. et al. NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice. Psychopharmacology 223, 345–355 (2012). https://doi.org/10.1007/s00213-012-2722-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-012-2722-0