Oruç YUNUSOĞLU, Muhammed Hamdi DEMIRKOL, Canan AKÜNAL TÜREL, Andleeb SHAHZADI, Mehmet BERKÖZ, Ahmet Gökhan AKKAN

Investigation of the pharmacological potential of myricetin on alcohol addiction in mice

Alcohol addiction is one of the leading causes which is associated with morbidity and mortality with outcomes in high healthcare and economic costs. Myricetin is a flavonoid that demonstrates therapeutic actions in many central nervous system diseases. In the current study, the conditioned place preference (CPP) tests were performed to examine the effects of myricetin on ethanol reward. During conditioning, intraperitoneal (i.p) administration of ethanol (2 g/kg) and serum physiologic were given on alternate days for 8 days. In order to evaluate the effect of myricetin on the development of alcohol addiction, myricetin was injected into mice 30 minutes before ethanol administration. Subsequently, a daily myricetin injection was performed to evaluate the effect of myricetin on the extinction of alcohol addiction. Finally, ethanol was administered 900 seconds after different dose myricetin administration, and reinstatement was evaluated immediately thereafter. Systemic ethanol (2 g/kg, i.p) administration significantly produced CPP. Myricetin (5 and 10 mg/kg, i.p) attenuated the development of ethanol addiction (p < 0.05). Systemic myricetin injections immediately after each extinction period precipitated extinction and decreased reinstatement (10 mg/kg, i.p, p < 0.05, respectively). Ethanol alone and in combination with myricetin did not change locomotor activity and motor coordination. As a result, it can be suggested that myricetin is effective in attenuating the rewarding effect of alcohol in mice and can be used for the adjunctive therapy for alcohol addiction. In addition, it will be appropriate to conduct mechanistic experimental studies regarding these results in the future.

PDF

___

[1] Heilig M, Augier E, Pfarr S, Sommer WH. Developing neuroscience-based treatments for alcohol addiction: A matter of choice? Transl Psychiatry 2019; 9: 255. [CrossRef]
[2] Tan HK, Yates E, Lilly K, Dhanda AD. Oxidative stress in alcohol-related liver disease. World J Hepatol 2020; 12(7):332-349. [CrossRef]
[3] Yunusoğlu O. Linalool attenuates acquisition and reinstatement and accelerates the extinction of nicotine- induced conditioned place preference in male mice. Am J Drug Alcohol Abuse 2021; 47(4):422-432. [CrossRef]
[4] Yanpar E, Yildirim M, Akkapulu M, Değirmenci U, Könen Adigüzel S, Yalin S, Yalın AE. Possible protective role of punicalagin on oxidative stress, inflammation and genotoxicity in ethanol-induced liver toxicity. J Res Pharm 2021; 25(5):600-608.
[5] Moriarty T, Bourbeau K, Zuhl M. Exercise and neural adaptations: Designing a novel treatment for alcohol addiction. Altern Ther Health Med 2020; 26(3):48-57.
[6] Pluta R, Januszewski S, Czuczwar SJ. Myricetin as a promising molecule for the treatment of post-ıschemic brain neurodegeneration. Nutrients 2021; 13(2): 342. [CrossRef]
[7] Deng H, Liu S, Pan D, Jia Y, Ma ZG. Myricetin reduces cytotoxicity by suppressing hepcidin expression in MES23.5 cells. Neural Regen Res 2021; 16(6):1105-1110. [CrossRef]
[8] Li J, Xiang H, Huang C, Lu J. Pharmacological actions of myricetin in the nervous system: a comprehensive review of preclinical studies in animals and cell models. Front Pharmacol. 2021; 12: 797298. [CrossRef]
[9] 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(12): 28377-28385. [CrossRef]
[10] Wang SC, Chen YC, Chen SJ, Lee CH, Cheng CM. Alcohol addiction, gut microbiota, and alcoholism treatment: A Review. Int J Mol Sci. 2020; 21(17): 6413. [CrossRef]
[11] Pantoni MM, Kim JL, Van Alstyne KR, Anagnostaras SG. MDMA and memory, addiction, and depression: Dose-effect analysis. Psychopharmacol. (Berl) 2022; 239(3): 935-949. [CrossRef]
[12] 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(8): 1836-1845. [CrossRef]
[13] Zhang XH, Ma ZG, Rowlands DK, Gou YL, Fok KL, Wong HY, Yu MK, Tsang LL, Mu L, Chen L, Yung WH, Chung YW, Zhang BL, Zhao H, Chan HC. Flavonoid myricetin modulates GABA(A) receptor activity through activation of Ca(2+) channels and CaMK-II pathway. Evid Based Complement Alternat Med. 2012; 2012: 758097. [CrossRef]
[14] Chang CJ, Tzeng TF, Liou SS, Chang YS, Liu IM. Myricetin ıncreases hepatic peroxisome proliferator activated receptor α protein expression and decreases plasma lipids and adiposity in rats. Evid Based Complement Alternat Med. 2012; 2012: 787152. [CrossRef] [15] Sadžak A, Vlašić I, Kiralj Z, Batarelo M, Oršolić N, Jazvinšćak Jembrek M, Kušen I, Šegota S. Neurotoxic effect of flavonol myricetin in the presence of excess copper. Molecules 2021; 26(4): 845. [CrossRef]
[16] Fusi F, Saponara S, Frosini M, Gorelli B, Sgaragli G. L-type Ca2+ channels activation and contraction elicited by myricetin on vascular smooth muscles. Naunyn Schmiedebergs Arch Pharmacol. 2003; 368(6): 470-478. [CrossRef]
[17] Kranzler HR, Soyka M. Diagnosis and Pharmacotherapy of alcohol use disorder: A review. Jama 2018; 320(8): 815-824. [CrossRef]
[18] McKendrick G, Graziane NM. Drug-ınduced conditioned place preference and ıts practical use in substance use disorder research. Front Behav Neurosci. 2020; 14: 582147. [CrossRef]
[19] Padula AE, Griffin WC, 3rd, Lopez MF, Nimitvilai S, Cannady R, McGuier NS, Chesler EJ, Miles MF, Williams RW, Randall PK, Woodward JJ, Becker HC, Mulholland PJ. KCNN genes that encode small-conductance Ca2+-activated K+ channels ınfluence alcohol and drug addiction. Neuropsychopharmacol. 2015; 40(8): 1928-1939. [CrossRef]
[20] Quiroga C, Barberena JJ, Alcaraz-Silva J, Machado S, Imperatori C, Yadollahpour A, Budde H, Yamamoto T, Telles-Correia D, Murillo-Rodríguez E. The role of peroxisome proliferator-activated receptor in addiction: A novel drug target. Curr Top Med Chem. 2021; 21(11): 964-975. [CrossRef]
[21] Allahverdiyev O, Nurten A, Enginar N. Assessment of rewarding and reinforcing properties of biperiden in conditioned place preference in rats. Behav Brain Res. 2011; 225(2): 642-645. [CrossRef]
[22] Khan Y, Pandy V. Morinda citrifolia Linn. (Noni) fruit extract attenuates ethanol seeking behavior in mouse runway paradigm. J Res Pharm. 2020; 24(5): 632-639. [CrossRef]
[23] Napier TC, Herrold AA, de Wit H. Using conditioned place preference to identify relapse prevention medications. Neurosci Biobehav Rev. 2013; 37(9 Pt A): 2081-2086. [CrossRef]
[24] Yunusoğlu O. Evaluation of the effects of quercetin on the rewarding property of ethanol in mice. Neurosci Lett. 2021: 136383. [CrossRef] [25] Xu C, Li R, Wu J. Effects of Yuanhu- Zhitong tablets on alcohol-induced conditioned place preference in mice. Biomed Pharmacother. 2021; 133: 110962. [CrossRef]
[26] Yunusoğlu O. Rewarding effect of ethanol-induced conditioned place preference in mice: Effect of the monoterpenoid linalool. Alcohol 2022; 98: 55-63. [CrossRef]
[27] Ramezani M, Darbandi N, Khodagholi F, Hashemi A. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease. Neural Regen Res. 2016; 11(12): 1976-1980. [CrossRef]
[28] Fan S, Gao X, Chen P, Li X. Myricetin ameliorates glucocorticoid-induced osteoporosis through the ERK signaling pathway. Life Sci. 2018; 207: 205-211. [CrossRef]
[29] Acevedo MB, Nizhnikov ME, Spear NE, Molina JC, Pautassi RM. Ethanol-induced locomotor activity in adolescent rats and the relationship with ethanol-induced conditioned place preference and conditioned taste aversion. Dev Psychobiol. 2013; 55(4):429-442. [CrossRef]
[30] Domi E, Domi A, Adermark L, Heilig M, Augier E. Neurobiology of alcohol seeking behavior. J Neurochem. 2021; 157(5): 1585-1614. [CrossRef]
[31] Banerjee N. Neurotransmitters in alcoholism: A review of neurobiological and genetic studies. Indian J Hum Genet. 2014; 20(1): 20-31. [CrossRef]
[32] Koob GF. A role for GABA mechanisms in the motivational effects of alcohol. Biochem Pharmacol. 2004; 68(8): 1515-1525. [CrossRef]
[33] Sun ZQ, Meng FH, Tu LX, Sun L. Myricetin attenuates the severity of seizures and neuroapoptosis in pentylenetetrazole kindled mice by regulating the of BDNF-TrkB signaling pathway and modulating matrix metalloproteinase-9 and GABA(A). Exp Ther Med. 2019; 17(4): 3083-3091. [CrossRef]
[34] Johnson KA, Lovinger DM. Allosteric modulation of metabotropic glutamate receptors in alcohol use disorder: Insights from preclinical investigations. Adv Pharmacol. 2020; 88: 193-232. [CrossRef]
[35] Tayfun Uzbay I, Oglesby MW. Nitric oxide and substance dependence. Neurosci Biobehav Rev. 2001; 25(1): 43-52. [CrossRef]
[36] Uzbay IT, Erden BF, Tapanyigit EE, Kayaalp SO. Nitric oxide synthase inhibition attenuates signs of ethanol withdrawal in rats. Life Sci. 1997; 61(22): 2197-2209. [CrossRef]
[37] Rostoka E, Baumane L, Isajevs S, Line A, Dzintare M, Svirina D, Sharipova J, Silina K, Kalvinsh I, Sjakste N. Effects of kaempferol and myricetin on inducible nitric oxide synthase expression and nitric oxide production in rats. Basic Clin Pharmacol Toxicol. 2010; 106(6): 461-466. [CrossRef]
[38] Berköz M, Yıldırım M, Yalın S, İlhan M, Yunusoğlu O. Myricetin inhibits angiotensin converting enzyme and induces nitric oxide production in HUVEC cell line. Gen Physiol Biophys. 2020; 39(3): 249-258. [CrossRef]
[39] Jang JH, Lee SH, Jung K, Yoo H, Park G. Inhibitory Effects of myricetin on lipopolysaccharide-ınduced neuroinflammation. Brain Sci 2020; 10(1): 32. [CrossRef]
[40] Le Foll B, Di Ciano P, Panlilio LV, Goldberg SR, Ciccocioppo R. Peroxisome proliferator-activated receptor (PPAR) agonists as promising new medications for drug addiction: Preclinical evidence. Curr Drug Targets 2013; 14(7): 768-776. [CrossRef]
[41] Xia SF, Le GW, Wang P, Qiu YY, Jiang YY, Tang X. Regressive effect of myricetin on hepatic steatosis in mice Fed a high-fat diet. Nutrients 2016; 8(12) : 799. [CrossRef]
42] Flores-Bonilla A, Richardson HN. Sex differences in the neurobiology of alcohol use disorder. Alcohol Res. 2020; 40(2): 04. [CrossRef] [43] Finn DA. The endocrine system and alcohol drinking in females. Alcohol Res. 2020; 40(2):02. [CrossRef]
[44] Yunusoğlu O. Resveratrol impairs acquisition, reinstatement and precipitates extinction of alcohol-induced place preference in mice. Neurol Res. 2021; 43(12): 985-994. [CrossRef]
[45] Yunusoğlu O. Linalool attenuates acquisition and reinstatement and accelerates the extinction of nicotine-induced conditioned place preference in male mice. Am J Drug Alcohol Abuse 2021; 47(4): 422-432. [CrossRef]
[46] Self DW. Neural substrates of drug craving and relapse in drug addiction. Ann Med. 1998; 30(4): 379-389. [CrossRef]
[47] Feltenstein MW, See RE, Fuchs RA. Neural substrates and circuits of drug addiction. Cold Spring Harb Perspect Med. 2021; 11(4): a039628. [CrossRef]
[48] Allahverdiyev O, Türkmen AZ, Nurten A, Sehirli I, Enginar N. Spontaneous withdrawal in intermittent morphine administration in rats and mice: effect of clonidine coadministration and sex-related differences. Turk J Med Sci. 2015; 45(6): 1380-1389.