The Noradrenergic System is Partly Involved in Resveratrol Antidepressant and Anti-Obsessive Like Effects in Mice Model

Document Type : Original paper


1 Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.

2 Isfahan Pharmaceutical Science Research Center, School of Pharmacy and Pharmaceutical sciences, Isfahan University of Medical Sciences, Isfahan, Iran.


Background and objectives: Resveratrol is a natural phenol in food particularly the skin of fruits like red grapes. It has shown biological, and antidepressant effects. The objective of the present study was to evaluate the role of adrenergic system on antidepressant and anti-obsessive effect of resveratrol. Methods: Male mice (weighing 27±2 g) were used. A tyrosine hydroxylase inhibitor, α-methyl-p-tyrosine (AMPT 100 mg/kg), α1 adrenergic receptors (AR) antagonist (prazosin, 1 mg/kg), α2-AR antagonist (yohimbine, 1 mg/kg), β-AR antagonist (propranolol, 2 mg/kg) and a tricyclic antidepressant (imipramine, 5 mg/kg), were injected before resveratrol (60 mg/kg). Locomotor activity, burring behavior during marble burring test, and immobility time during forced swimming test (FST) were evaluated. Results: No significant difference was observed in the locomotor activity between groups. The immobility time increased following pretreatment with AMPT (147.3±6.35s vs resveratrol alone 85.67±4.51s, p <0.001); marble burring behavior increased significantly, indicating the possible role of norepinephrine in resveratrol antidepressant and anti-obsessive-like effects. Propranolol (163.8±8.25 s, p <0.001) and yohimbine (151.0±6.47s, p=0.0030) pretreatment increased immobility in the FST compared to resveratrol. Pretreatment with prazosin did not cause important change in FST. Pretreatment with propranolol slightly increased marble burring behavior while no changes were observed following yohimbine or prazosin administration. Imipramine pretreatment did not have additive antidepressant effect with resveratrol and increased immobility time (136.1±16.88 s, p=0.014 vs resveratrol). Conclusion: Resveratrol antidepressant-like effect is partly mediated by the noradrenergic system, and interaction with β-AR and α2-AR. Additionally, resveratrol anti-obsessive-like property involves noradrenergic system but not the β or α-AR.


Main Subjects

[1] Shigemura J, Ursano RJ, Morganstein JC, Kurosawa M, Benedek DM. Public responses to the novel 2019 coronavirus (2019-nCoV) in Japan: mental health consequences and target populations. Psychiatry Clin Neurosci. 2020; 74(4): 281–282.
[2] Radua J, Van den Heuvel OA, Surguladze S, Mataix-Cols D. Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders. Arch Gen Psychiatry. 2010; 67(7): 701–711.
[3] Mesripour A, Almasi M. Flaxseed prevents interferon-alpha induced depressive behavior in mice: the α-linolenic acid is essential. Res J Pharmacogn. 2021; 8(1): 63–71.
[4] Rafieian-Kopaei M. Medicinal plants and the human needs. J Herbmed Pharmacol. 2012; 1(1): 1–2.
[5] Ogle WO, Speisman RB, Ormerod BK. Potential of treating age related depression and cognitive decline with nutraceutical approaches: a mini-review. Gerontology. 2013; 59(1): 23–31.
[6] Hurley LL, Akinfiresoye L, Nwulia E, Kamiya A, Kulkarni AA, Tizabi Y. Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF. Behav Brain Res. 2013; 239: 27–30.
[7] Finnell JE, Lombard CM, Melson MN, Singh NP, Nagarkatti M, Nagarkatti P, Fadel JR, Wood CS, Wood SK. The protective effects of resveratrol on social stress-induced cytokine release and depressive-like behavior. Brain Behav Immun. 2017; 59: 147–157.
[8] Rania FA, Rehab Fawzy A, Omar AHA F, Salma AE, Alyaa FH. Combined hepatoprotective and antidepressant effects of resveratrol in an acute model of depression. Bull Fac Pharm Cairo Univ. 2014; 52(2): 191–197.
[9] Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov. 2006; 5(6): 493–506.
[10] Bradamante S, Barenghi L, Piccinini F, Bertelli AA, De Jonge R, Beemster P, De Jong DW. Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Eur J Pharmacol. 2003; 465(1-2): 115–123.
[11] Wu X, Xu Y, Zhu B, Liu Q, Yao Q, Zhao G. Resveratrol induces apoptosis in SGC-7901 gastric cancer cells. Oncol Lett. 2018; 16(3): 2949–2956.
[12] Tresguerres IF, Tamimi F, Eimar H, Barralet J, Torres J, Blanco L, Tresguerres JAF. Resveratrol as anti-aging therapy for age-related bone loss. Rejuvenation Res. 2014; 17(5): 439–445.
[13] Maletic V, Eramo A, Gwin K, Offord SJ, Duffy RA. The role of norepinephrine and its α-adrenergic receptors in the pathophysiology and treatment of major depressive disorder and schizophrenia: a systematic review. Front Psychiatry. 2017; 8: 1–12.
[14] Hein L. Adrenoceptors and signal transduction in neurons. Cell Tissue Res. 2006; 326(2): 541–551.
[15] Brocardo PS, Budni J, Kaster MP, Santos ARS, Rodrigues ALS. Folic acid administration produces an antidepressant-like effect in mice: evidence for the involvement of the serotonergic and noradrenergic systems. Neuropharmacology. 2008; 54(2): 464–473.
[16] Mesripour A, Sajadiyan S, Hajhashemi V. Antidepressant-like effect of vitamin B6 in mice forced swimming test and the possible involvement of the noradrenergic system. J Rep Pharm Sci. 2019; 8(2): 133–138.
[17] Xu Y, Wang Z, You W, Zhang X, Li S, Barish PA, Vernon MM, Du X, Li G, Pan J, Ogle WO. Antidepressant-like effect of trans-resveratrol: Involvement of serotonin and noradrenaline system. Eur Neuropsychopharmacol. 2010; 20(6): 405–413.
[18] Gad SC, Cassidy CD, Aubert N, Spainhour B, Robbe H. Nonclinical vehicle use in studies by multiple routes in multiple species. Int J Toxicol. 2006; 25(6): 499–521.
[19] Mesripour A, Hajhashemi V, Kuchak A. Effect of concomitant administration of three different antidepressants with vitamin B6 on depression and obsessive compulsive disorder in mice models. Res Pharm Sci. 2017; 12(1): 46–52.
[20] Mesripour A, Kaviyanpour M, Hajhashemi V. Antidepressant-like effect of minocycline in mice forced swimming test: minor involvement of the noradrenergic system. Thai J Pharm Sci. 2019; 43(3): 125–130.
[21] Gu Z, Chu L, Han Y. Therapeutic effect of resveratrol on mice with depression. Exp Ther Med. 2019; 17(4): 3061–3064.
[22] Zill P, Baghai TC, Engel R, Zwanzger P, Schüle C, Minov C, Behrens S, Bottlender R, Jäger M, Rupprecht R, Möller HJ, Ackenheil M, Bondy B. Beta-1-adrenergic receptor gene in major depression: influence on antidepressant treatment response. Am J Med Genet B Neuropsychiatr Genet. 2003; 120B(1): 85–89.
[23] Manji HK, Lenox RH. Signaling: cellular insights into the pathophysiology of bipolar disorder. Biol Psychiatry. 2000; 48(6): 518–530.
[24] O'Neill MF, Osborne DJ, Woodhouse SM, Conway MW. Selective imidazoline I2 ligands do not show antidepressant-like activity in the forced swim test in mice. J Psychopharmacol. 2001; 15(1): 18–22.
[25] Invernizzi RW, Garattini S. Role of presynaptic alpha2-adrenoceptors in antidepressant action: recent findings from microdialysis studies. Prog Neuropsychopharmacol Biol Psychiatry. 2004; 28(5): 819–827.
[26] Zhang HT, Whisler LR, Huang Y, Xiang Y, O'Donnell JM. Postsynaptic alpha-2 adrenergic receptors are critical for the antidepressant-like effects of desipramine on behavior. Neuropsychopharmacology. 2009; 34(4): 1067–1077.
[27] Deacon RMJ. Digging and marble burying in mice: simple methods for in vivo identification of biological impacts. Nat Protoc. 2006; 1(1): 122–124.
[28] Gawali NB, Chowdhury AA, Kothavade PS, Bulani VD, Nagmoti DM, Juvekar AR. Involvement of nitric oxide in anti compulsive‑like effect of agmatine on marble‑burying behaviour in mice. Eur J Pharmacol. 2016; 770: 165–171.
[29] Sugimoto Y, Tagawa N, Kobayashi Y, Hotta Y, Yamada J. Effects of the serotonin and noradrenaline reuptake inhibitor (SNRI) milnacipran on marble burying behavior in mice. Biol Pharm Bull. 2007; 30(12): 2399–2401.
[30] Merali Z, Levac C, Anisman H. Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice. Biol Psychiatry. 2003; 54(5): 552–565.
[31] Skelly MJ, Weiner JL. Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain Behav. 2014; 4(4): 468–483.
[32] Rasmussen DD, Kincaid CL, Froehlich JC. Prazosin prevents increased anxiety behavior that occurs in response to stress during alcohol deprivations. Alcohol Alcohol. 2017; 52(1): 5–11.
[33] Koo MS, Kim EJ, Roh D, Kim CH. Role of dopamine in the pathophysiology and treatment of obsessive-compulsive disorder. Expert Rev Neurother. 2010; 10(2): 275–290.