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Effect of (4a) a novel 5-HT3 receptor antagonist on chronic unpredictable mild stress induced depressive-like behavior in mice: an approach using behavioral tests battery

  • Yeshwant Kurhe EMAIL logo , Radhakrishnan Mahesh , Deepali Gupta and Devadoss Thangaraj
Published/Copyright: March 29, 2014

Abstract

Background: The inconsistent therapeutic outcome necessitates designing and identifying novel therapeutic interventions for depression. Hence, the present study deals with the investigation of antidepressant-like effects of a novel 5-HT3 receptor antagonist (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a) on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alterations.

Methods: Animals were subjected to different stressors for a period of 28 days. On day 15 after the subsequent stress procedure, mice were administered with (4a) (2 and 4 mg/kg p.o.), escitalopram (10 mg/kg p.o.), or vehicle (10 mL/kg p.o.) until day 28 along with the CUMS. Thereafter, behavioral battery tests like locomotor score, sucrose preference test, forced swim test (FST), tail suspension test (TST), and elevated plus maze (EPM) were performed. Biochemical assays like lipid peroxidation, nitrite levels, reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were estimated in the mice brain homogenate.

Results: (4a) Dose dependently attenuated the behavioral alterations by increasing the sucrose consumption, reducing the immobility time in FST and TST, increasing the open arm number of entries and time in EPM. Furthermore, biochemical alterations were reversed by (4a) as examined by reduced lipid peroxidation and nitrite levels and elevated antioxidant enzyme levels like GSH, catalase and SOD.

Conclusions: (4a) exhibits antidepressant potential by reversing the CUMS induced behavioral and biochemical changes in mice.


Corresponding author: Yeshwant Kurhe, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan-333031, India, Phone: +91 8094693209, E-mail:

Acknowledgments

We are thankful to Birla Institute of Technology and Science (BITS), Pilani, India, for providing support and the research facilities to pursue this work.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article.

Research funding: None declared.

Employment or leadership: None declared.

Honorarium: None declared.

References

1. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron 2002;34:13–25.10.1016/S0896-6273(02)00653-0Search in Google Scholar

2. Greenberg P, Corey-Lisle PK, Birnbaum H, Marynchenko M, Claxton A. Economic implications of treatment-resistant depression among employees. Pharmacoeconomics 2004;22:363–73.10.2165/00019053-200422060-00003Search in Google Scholar

3. Willner P. Chronic mild stress (CMS) revisited: consistency and behavioral-neurobiological concordance in the effects of CMS. Neuropsychobiology 2005;52:90–110.10.1159/000087097Search in Google Scholar

4. Fontella FU, Siqueria IR, Vasconcellos AP, Tabajara AS, Netto CA, Dalmaz C. Repeated restraint stress induces oxidative damage in rat hippocampus. Neurochem Res 2005;30:105–11.10.1007/s11064-004-9691-6Search in Google Scholar

5. Bhattacharya SK, Muruganandam AV. Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress. Pharmacol Biochem Behav 2003;75:547–55.10.1016/S0091-3057(03)00110-2Search in Google Scholar

6. Bilici M, Efe H, Koroglu MA, Uydu HA, Bekaroglu M, Deger O. Antioxidative enzyme activities and lipid peroxidation in major depression: alterations by antidepressant treatments. J Affect Disord 2001;64:43–51.10.1016/S0165-0327(00)00199-3Search in Google Scholar

7. Deakin JF. Depression and 5-HT. Int Clin Psychopharmacol 1991;6:23–8.10.1097/00004850-199112003-00002Search in Google Scholar

8. Adell A, Castro A, Celada P, Bortolozzi A, Pazos A, Artigas F. Strategies for producing faster acting antidepressants. Drug Discov Today 2005;10:578–85.10.1016/S1359-6446(05)03398-2Search in Google Scholar

9. Herrstedt J, Dombernowsky P. Anti-emetic therapy in cancer chemotherapy: current status. Basic Clin Pharmacol Toxicol 2007;101:143–50.10.1111/j.1742-7843.2007.00122.xSearch in Google Scholar PubMed

10. Greenshaw AJ, Silverstone H. The non-antiemetic uses of serotonin 5-HT3 receptor antagonists. Drugs 1997;53:20–39.10.2165/00003495-199753010-00003Search in Google Scholar PubMed

11. Faerber L, Drechsler S, Ladenburger S, Gschaidmeier WH, Fischer W. The neuronal 5-HT3 receptor network after 20 years of research-evolving concepts in management of pain and inflammation. Eur J Pharmacol 2007;560:1–8.10.1016/j.ejphar.2007.01.028Search in Google Scholar

12. Eisensamer B, Rammes G, Gimpl G, Ferrari U, Hapfelmeier G, Rupprecht R. Antidepressants are functional antagonists at the serotonin type 3 (5-HT3) receptor. Mol Psychiatr 2003;8:994–1007.10.1038/sj.mp.4001314Search in Google Scholar

13. Mahesh R, Devadoss T, Pandey DK, Bhatt S, Yadav SK. Design, synthesis and structure-activity relationship of novel quinoxalin-2-carboxamides as 5-HT3 receptor antagonists for the management of depression. Bioorg Med Chem Lett 2010;20:6773–6.10.1016/j.bmcl.2010.08.128Search in Google Scholar

14. Mahesh R, Kumar B, Jindal A, Bhatt S, Devadoss T, Pandey DK. Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT3 receptor antagonist: an investigation in behavior-based rodent models of depression. Ind J Pharmacol 2012;44:560–5.10.4103/0253-7613.100371Search in Google Scholar

15. Qing-Qiu M, Siu-Po I, Kam-Ming K, Sam-Hip T, Chun-Tao C. Peony glycosides produce antidepressant-like action in mice exposed to chronic unpredictable mild stress: effects on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor. Prog Neuropsychopharmacol Biol 2009;33:1211–6.10.1016/j.pnpbp.2009.07.002Search in Google Scholar

16. Casarotto PC, Andreatini R. Repeated paroxetine treatment reverses anhedonia induced in rats by chronic mild stress or dexamethasone. Eur Neuropsychopharmacol 2007;17:735–42.10.1016/j.euroneuro.2007.03.001Search in Google Scholar

17. Engeland CG, Kavaliers M, Ossenkopp KP. Sex differences in the effects of muramyl dipeptide and lipopolysaccharide on locomotor activity and the development of behavioral tolerance in rats. Pharmacol Biochem Behav 2003;74:433–47.10.1016/S0091-3057(02)01024-9Search in Google Scholar

18. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977;229:327–36.Search in Google Scholar

19. Steru L, Chermat R, Thierry B, Simon P. The tail suspension test: a new method for screening antidepressant drugs. Psychopharmacology 1985;85:367–70.10.1007/BF00428203Search in Google Scholar

20. Rodgers RJ, Dalvi A. Anxiety, defence and the elevated plus-maze. Neurosci Biobehav Rev 1997;21:801–10.10.1016/S0149-7634(96)00058-9Search in Google Scholar

21. Kumar B, Kuhad A, Chopra K. Neuropsychopharmacological effect of sesamol in unpredictable chronic mild stress model of depression: behavioral and biochemical evidences. Psychopharmacology 2011;214:819–28.10.1007/s00213-010-2094-2Search in Google Scholar PubMed

22. Wills ED. Mechanism of lipid peroxide formation in animal tissues. Biochem J 1996;99:667–76.10.1042/bj0990667Search in Google Scholar

23. Koller A. Total serum protein. In: Kaplan LA, Pesce AJ, editors. Clinical chemistry – theory, analysis, and correlation. St. Louis: Mosby Company, 1984:1316–9.Search in Google Scholar

24. Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR. Bromo-benze induced liver necrosis: protective role of glutathione and evidence for 3,4-bromobenzenoxide as the hepatotoxic metabolite. Pharmacology 1974;11:151–69.10.1159/000136485Search in Google Scholar

25. Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15 N] nitrate in biological fluids. Anal Biochem 1982;126:131–8.10.1016/0003-2697(82)90118-XSearch in Google Scholar

26. Claiborne A. Catalase activity. In: Greenwald RA, editor. Handbook of methods for oxygen radical research, 2nd ed. Boca Raton, FL: CRC Press, 1985:283–4.Search in Google Scholar

27. Mishra HP, Fridovich I. The role of superoxide anion in the auto-oxidation of the epinephrine and a simple assay for superoxide dismutase. J Biol Chem 1972;247:3170–5.10.1016/S0021-9258(19)45228-9Search in Google Scholar

28. Willner P. The validity of animal models of depression. Psychopharmacology 1984;83:1–16.10.1007/BF00427414Search in Google Scholar PubMed

29. Luo DD, An SC, Zhang X. Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress. Brain Res Bull 2008;77:8–12.10.1016/j.brainresbull.2008.05.010Search in Google Scholar PubMed

30. Li S, Wang C, Wang M, Li W, Matsumoto K, Tang Y. Antidepressant like effects of piperine in chronic mild stress treated mice and its possible mechanisms. Life Sci 2007;80:1373–81.10.1016/j.lfs.2006.12.027Search in Google Scholar PubMed

31. Rajkumar R, Mahesh R. The auspicious role of 5-HT3 receptors in depression: a probable neuronal target. J Psychopharmacol 2010;24:455–69.10.1177/0269881109348161Search in Google Scholar PubMed

32. Cryan JF, Valentino RJ, Lucki I. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 2005;29:547–69.10.1016/j.neubiorev.2005.03.008Search in Google Scholar PubMed

33. Strekalova T, Gorenkova N, Schunk E, Dolgov O, Bartsch D. Selective effects of citalopram in a mouse model of stress-induced anhedonia with a control for chronic stress. Behav Pharmacol 2006;17:271–87.10.1097/00008877-200605000-00008Search in Google Scholar PubMed

34. Bekris S, Antoniou K, Daskas S, Papadopoulou-Daifoti Z. Behavioural and neurochemical effects induced by chronic mild stress applied to two different rat strains. Behav Brain Res 2005;161:45–59.10.1016/j.bbr.2005.01.005Search in Google Scholar

35. Hogg S. A review of the validity and variability of the elevated plus maze as an animal model of anxiety. Pharmacol Biochem Behav 1996;54:21–30.10.1016/0091-3057(95)02126-4Search in Google Scholar

36. Liu J, Wang X, Mori A. Immobilization stress-induced antioxidant defence changes in rat plasma, effect of treatment with reduced glutathione. Int J Biochem 1994;26:511–7.10.1016/0020-711X(94)90008-6Search in Google Scholar

37. Liu J, Wang X, Shigenaga MK, Yeo HC, Mori A, Ames BN. Immobilization stress causes oxidative damage to lipid, protein, and DNA in the brain of rats. FASEB J 1996;10:1532–8.10.1096/fasebj.10.13.8940299Search in Google Scholar

38. Matsumoto K, Yobimoto K, Huong NT, Abdel-Fattah M, Hien TV, Watanabe H. Psychological stress-induced enhancement of brain lipid peroxidation via nitric oxide systems and its modulation by anxiolytic and anxiogenic drugs in mice. Brain Res 1999;839:74–84.10.1016/S0006-8993(99)01715-1Search in Google Scholar

39. Sunanda Rao BS, Raju TR. Restraint stress-induced alterations in the levels of biogenic amines, amino acids, and AChE activity in the hippocampus. Neurochem Res 2000;25:1547–52.10.1023/A:1026606201069Search in Google Scholar

40. Torres IL, Gamaro GD, Vasconcellos AP, Silveira R, Dalmaz C. Effects of chronic restraint stress on feeding behavior and on monoamine levels in different brain structures in rats. Neurochem Res 2002;27:519–25.10.1023/A:1019856821430Search in Google Scholar

41. Park JW, Youn YC, Kwon OS, Jang YY, Han ES, Lee CS. Protective effect of serotonin on 6-hydroxydopamine- and dopamine-induced oxidative damage of brain mitochondria and synaptosomes and PC12 cells. Neurochem Int 2002;40:223–33.10.1016/S0197-0186(01)00072-9Search in Google Scholar

42. Eren I, Nazıroglu M, Demirdaş A, Çelik O, Uguz AC, Altunbaşak A, et al. Venlafaxine modulates depression-induced oxidative stress in brain and medulla of rat. Neurochem Res 2007;32:497–505.10.1007/s11064-006-9258-9Search in Google Scholar PubMed

43. Eren I, Nazıroglu M, Demirdaş A. Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain. Neurochem Res 2007;32:1188–95.10.1007/s11064-007-9289-xSearch in Google Scholar PubMed

Received: 2013-11-28
Accepted: 2014-2-14
Published Online: 2014-3-29
Published in Print: 2015-1-1

©2015 by De Gruyter

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