• Sakthivel G Department of Physiology, Dr. A.L.M Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai - 600 113, Tamil Nadu, India.
  • Deva Karunya M Department of Physiology, Dr. A.L.M Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai - 600 113, Tamil Nadu, India.
  • Prajisha P Department of Physiology, Dr. A.L.M Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai - 600 113, Tamil Nadu, India.
  • Keerthipriya Cs Department of Physiology, Dr. A.L.M Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai - 600 113, Tamil Nadu, India.
  • Ravindran R Department of Physiology, Dr. A.L.M Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai - 600 113, Tamil Nadu, India.


 Objective: The present study is designed to investigate the effects of chronic unpredictable stress (CUS) on electrophysiological and behavioral alterations in male Wistar albino rats and its ameliorating effect by myricetin-microemulsion (MYR-ME).

Materials and Methods: Adult Wistar male albino rats were exposed to CUS for 21 days and treated with MYR-ME (10 mg/kg) for 21 days by oral administration. All the experimental animals were tested for anxiety and cognitive behavior by open-field behavior, light/dark test, eight-arm radial maze, spontaneous alteration T-maze, novel object recognition test, plasma corticosterone level, and electrophysiological activity.

Results: The rats which were exposed to CUS showed memory impairment, increased anxiety, decreased novel explorations, deleterious effect on decision-making, increased corticosterone level, increased brain wave frequency and amplitude, and also heart rate. Whereas, CUS with MYR-ME-treated group showed a protective effect against CUS-induced behavioral alterations, electrophysiological activity, and corticosterone levels, which is characterized by the enhancement of cognitive function, decreased anxiety and improved decision-making, novel exploration, decreased corticosterone, and electrophysiological activity.

Conclusion: From the present study, it is shown that MYR-ME may act as a potential anxiolytic and nootropic compound against CUS-induced alterations.

Keywords: Chronic unpredictable stress, Myricetin-microemulsion, Cognitive behavior, anxiety, Learning and memory, Electrophysiology.


1. Gouirand AM, Matuszewich L. The effects of chronic unpredictable stress on male rats in the water maze. Physiol Behav 2005;86:21-31.
2. Gopalan G, Bannon W, Dean-Assael K, Fuss A, Gardner L, LaBarbera B, et al. Multiple family groups: An engaging intervention for child welfare-involved families. Child Welfare 2011;90:135-56.
3. Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 2002;22:6810-8.
4. Rao VR, Finkbeiner S. NMDA and AMPA receptors: Old channels, new tricks. Trends Neurosci 2007;30:284-91.
5. Wang H, Hu Y, Tsien JZ. Molecular and systems mechanisms of memory consolidation and storage. Prog Neurobiol 2006;79:123-35.
6. Park CR, Campbell AM, Diamond DM. Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in adult rats. Biol Psychiatry 2001;50:994-1004.
7. Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T, et al. Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J Neurosci 2000;20:1568-74.
8. Liu D, Zhang Q, Gu J, Wang X, Xie K, Xian X, et al. Resveratrol prevents impaired cognition induced by chronic unpredictable mild stress in rats. Prog Neuropsychopharmacol Biol Psychiatry 2014;49:21-9.
9. Matuszewich L, Karney JJ, Carter SR, Janasik SP, O’Brien JL, Friedman RD, et al. The delayed effects of chronic unpredictable stress on anxiety measures. Physiol Behav 2007;90:674-81.
10. Zhong X, Hilton HJ, Gates GJ, Jelic S, Stern Y, Bartels MN, et al. Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol 2005;98:2024-32.
11. Loganathan S, Rathinasamy S. Alteration in memory and electroencephalogram waves with sub-acute noise stress in albino rats and safeguarded by scoparia dulcis. Pharmacogn Mag 2016;12:S7-S13.
12. Kesselheim AS, Hwang TJ, Franklin JM. Two decades of new drug development for central nervous system disorders. Nat Rev Drug Discov 2015;14:815-6.
13. Ong KC, Khoo HE. Biological effects of myricetin. Gen Pharmacol 1997;29:121-6.
14. Yoshikawa M, Shimada H, Nishida N, Li Y, Toguchida I, Yamahara J, et al. Antidiabetic principles of natural medicines. II. Aldose reductase and alpha-glucosidase inhibitors from brazilian natural medicine, the leaves of Myrcia multiflora DC. (Myrtaceae): Structures of myrciacitrins I and II and myrciaphenones A and B. Chem Pharm Bull (Tokyo) 1998;46:113-9.
15. Chen W, Li Y, Li J, Han Q, Ye L, Li A. Myricetin affords protection against peroxynitrite-mediated dna damage and hydroxyl radical formation. Food Chem Toxicol 2011;49:2439-44.
16. Semwal DK, Semwal RB, Combrinck S, Viljoen A. Myricetin: A dietary molecule with diverse biological activities. Nutrients 2016;8:90.
17. Hagenacker T, Hillebrand I, Wissmann A, Büsselberg D, Schäfers M. Anti-allodynic effect of the flavonoid myricetin in a rat model of neuropathic pain: Involvement of p38 and protein kinase C mediated modulation of ca²+ channels. Eur J Pain 2010;14:992-8.
18. Mohan M, Jadhav SS, Kasture VS, Kasture SB. Effect of myricetin on behavioral paradigms of anxiety. Pharm Biol 2009;47:927-31.
19. Yao Y, Lin G, Xie Y, Ma P, Li G, Meng Q, et al. Preformulation studies of myricetin: A natural antioxidant flavonoid. Pharmazie 2014;69:19-26.
20. Hoar TP, Schulman JH. Transparent water-in-oil dispersions: The oleopathic hydro-micelle. Nature 1943;152:102-3.
21. Wang S, Ye T, Zhang X, Yang R, Yi X. Myricetin microemulsion for oral drug delivery : Formulation optimization, in situ intestinal absorption and in-vivo evaluation. Asian J Pharm Sci 2013;8:18-25.
22. Katz RJ. Animal model of depression: Pharmacological sensitivity of a hedonic deficit. Pharmacol Biochem Behav 1982;16:965-8.
23. Prut L, Belzung C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur J Pharmacol 2003;463:3-3.
24. Arrant AE, Schramm-Sapyta NL, Kuhn CM. Use of the light/dark test for anxiety in adult and adolescent male rats. Behav Brain Res 2013;256:119-27.
25. Olton DS, Samuelson RJ. Remembrance of places passed: Spatial memory in rats. J Exp Psychol Anim Behav Process 1976;2:97-116.
26. Deacon RM, Rawlins JN. T-maze alternation in the rodent. Nat Protoc 2006;1:7-12.
27. Antunes M, Biala G. The novel object recognition memory: Neurobiology, test procedure, and its modifications. Cogn Process 2012;13:93-110.
28. Thandapilly SJ, Louis XL, Behbahani J, Movahed A, Yu L, Fandrich R, et al. Reduced hemodynamic load aids low-dose resveratrol in reversing cardiovascular defects in hypertensive rats. Hypertens Res 2013;36:866-72.
29. Choudhary AK, Sundareswaran L, Devi RS. Effects of aspartame on the evaluation of electrophysiological responses in wistar albino rats. J Taibah Univ Sci 2016;10:505-12.
30. Rai AR, Madhyastha S, Prabhu LV, Saralaya VV, Sahu SS. Resveratrol reverses the restraint stress-induced cognitive dysfunction involving brain antioxidant system in rats. Int J Pharm Pharm Sci 2014;6:768-72.
31. Chiba S, Numakawa T, Ninomiya M, Richards MC, Wakabayashi C, Kunugi H. Chronic restraint stress causes anxiety-and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2012;39:112-9.
32. Ma Z, Wang G, Cui L, Wang Q. Myricetin attenuates depressant-like behavior in mice subjected to repeated restraint stress. Int J Mol Sci 2015;16:28377-85.
33. Riaz MS, Bohlen MO, Gunter BW, Quentin H, Stockmeier CA, Paul IA, et al. Attenuation of social interaction-associated ultrasonic vocalizations and spatial working memory performance in rats exposed to chronic unpredictable stress. Physiol Behav 2015;152:128-34.
34. Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: The impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 2011;13:22-37.
35. Chang Y, Chang CY, Wang SJ, Huang SK. Myricetin inhibits the release of glutamate in rat cerebrocortical nerve terminals. J Med Food 2015;18:516-23.
36. Dhanraj V, Manivasagam T, Karuppaiah J. Myricetin isolated from turbinaria ornata ameliorates rotenone induced parkinsonism in drosophila melanogaster. Int J Pharm Pharm Sci 2017;9:1-6.
37. Vidyashree HM, Malathi S, Ravindran R. Impaired object recognition memory and acetylcholinesterase activity in animal model of post-traumatic stress disorder-restored by Eclipta alba Linn. A dietary herb. Asian J Pharm Clin Res. 2016;9: 117–121.
38. Singh P, Thakur MK. Reduced recognition memory is correlated with decrease in DNA methyltransferase1 and increase in histone deacetylase2 protein expression in old male mice. Biogerontology 2014;15:339-46.
39. Kazlauckas V, Kalinine E, Leke R, Oses JP, Nunes F, Espinosa J, et al. Distinctive effects of unpredictable subchronic stress on memory, serum corticosterone and hippocampal BDNF levels in high and low exploratory mice. Behav Brain Res 2011;218:80-6.
40. Hollenstein T, McNeely A, Eastabrook J, Mackey A, Flynn J. Sympathetic and parasympathetic responses to social stress across adolescence. Dev Psychobiol 2012;54:207-14.
41. van Lier H, Drinkenburg WH, van Eeten YJ, Coenen AM. Effects of diazepam and zolpidem on EEG beta frequencies are behavior-specific in rats. Neuropharmacology 2004;47:163-74.
42. Karst H. Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells. J Neurophysiol 2005;94:3479-86.
43. Sharma HS, Dey PK. EEG changes following increased blood-brain barrier permeability under long-term immobilization stress in young rats. Neurosci Res 1988;5:224-39.
44. Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H. Three distinct neuroprotective functions of myricetin against glutamate-induced neuronal cell death: Involvement of direct inhibition of caspase-3. J Neurosci Res 2008;86:1836-45.
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How to Cite
G, S., D. Karunya M, P. P, K. Cs, and R. R. “CHRONIC UNPREDICTABLE STRESS-INDUCED BEHAVIORAL AND ELECTROPHYSIOLOGICAL ALTERATIONS AND ITS AMELIORATIVE EFFECT BY MYRICETIN MICROEMULSION”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 11, no. 3, Mar. 2018, pp. 124-31, doi:10.22159/ajpcr.2018.v11i3.23364.
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