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BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2019

Open Access 01-12-2019 | Anxiety | Research article

Methanol extract of semen Ziziphi Spinosae attenuates ethanol withdrawal anxiety by improving neuropeptide signaling in the central amygdala

Authors: Li Bo Li, Young Woo Kim, Yu Hua Wang, Li Bai, Xiao Dong Zhu, Zheng Lin Zhao, Chul Won Lee, Yu Jiao, Tong Wu, Zhen Zhen Cai, Sang Chan Kim, Won G. An, Chae Ha Yang, Guang Cheng Cui, Rong Jie Zhao

Published in: BMC Complementary Medicine and Therapies | Issue 1/2019

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Abstract

Background

Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways.

Methods

Male Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays.

Results

MESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS.

Conclusions

These results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.
Appendix
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Literature
1.
Garbusow M, Sebold M, Beck A, Heinz A. Too difficult to stop: mechanisms facilitating relapse in alcohol dependence. Neuropsychobiology. 2014;70(2):103–10.PubMedCrossRef
2.
3.
Heilig M, Egli M, Crabbe JC, Becker HC. Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol. 2010;15(2):169–84.PubMedPubMedCentralCrossRef
4.
Kang S, Li J, Zuo W, Fu R, Gregor D, Krnjevic K, Bekker A, Ye JH. Ethanol withdrawal drives anxiety-related behaviors by reducing M-type Potassium Channel activity in the lateral Habenula. Neuropsychopharmacology. 2017;42(9):1813–24.PubMedPubMedCentralCrossRef
5.
Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, Koob GF. Increased ethanol self-administration and anxiety-like behavior during acute ethanol withdrawal and protracted abstinence: regulation by corticotropin-releasing factor. Alcohol Clin Exp Res. 2002;26(10):1494–501.PubMedCrossRef
6.
Merali Z, Michaud D, McIntosh J, Kent P, Anisman H. Differential involvement of amygdaloid CRH system(s) in the salience and valence of the stimuli. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27(8):1201–12.CrossRef
7.
Menzaghi F, Rassnick S, Heinrichs S, Baldwin H, Pich EM, Weiss F, Koob GF. The role of corticotropin-releasing factor in the anxiogenic effects of ethanol withdrawal. Ann N Y Acad Sci. 1994;739:176–84.PubMedCrossRef
8.
Chae Y, Yeom M, Han JH, Park HJ, Hahm DH, Shim I, Lee HS, Lee H. Effect of acupuncture on anxiety-like behavior during nicotine withdrawal and relevant mechanisms. Neurosci Lett. 2008;430(2):98–102.PubMedCrossRef
9.
Pleil KE, Rinker JA, Lowery-Gionta EG, Mazzone CM, McCall NM, Kendra AM, Olson DP, Lowell BB, Grant KA, Thiele TE, Kash TL. NPY signaling inhibits extended amygdala CRF neurons to suppress binge alcohol drinking. Nat Neurosci. 2015;18(4):545–52.PubMedPubMedCentralCrossRef
10.
Eisenhardt M, Hansson AC, Spanagel R, Bilbao A. Chronic intermittent ethanol exposure in mice leads to an up-regulation of CRH/CRHR1 signaling. Alcohol Clin Exp Res. 2015;39(4):752–62.PubMedCrossRef
11.
Rassnick S, Heinrichs SC, Britton KT, Koob GF. Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal. Brain Res. 1993;605(1):25–32.PubMedCrossRef
12.
Lowery-Gionta EG, Navarro M, Li C, Pleil KE, Rinker JA, Cox BR, Sprow GM, Kash TL, Thiele TE. Corticotropin releasing factor signaling in the central amygdala is recruited during binge-like ethanol consumption in C57BL/6J mice. J Neurosci. 2012;32(10):3405–13.PubMedPubMedCentralCrossRef
13.
Lowery EG, Spanos M, Navarro M, Lyons AM, Hodge CW, Thiele TE. CRF-1 antagonist and CRF-2 agonist decrease binge-like ethanol drinking in C57BL/6J mice independent of the HPA axis. Neuropsychopharmacology. 2010;35(6):1241–52.PubMedPubMedCentralCrossRef
14.
15.
Filaferro M, Ruggieri V, Novi C, Calò G, Cifani C, Micioni Di Bonaventura MV, Sandrini M, Vitale G. Functional antagonism between nociceptin/orphanin FQ and corticotropin-releasing factor in rat anxiety-related behaviors: involvement of the serotonergic system. Neuropeptides. 2014;48(4):189–97.PubMedCrossRef
16.
Economidou D, Cippitelli A, Stopponi S, Braconi S, Clementi S, Ubaldi M, Martin-Fardon R, Weiss F, Massi M, Ciccocioppo R. Activation of brain NOP receptors attenuates acute and protracted alcohol withdrawal symptoms in the rat. Alcohol Clin Exp Res. 2011;35(4):747–55.PubMedPubMedCentralCrossRef
17.
Ciccocioppo R, Economidou D, Fedeli A, Angeletti S, Weiss F, Heilig M, Massi M. Attenuation of ethanol self-administration and of conditioned reinstatement of alcohol-seeking behaviour by the antiopioid peptide nociceptin/orphanin FQ in alcohol-preferring rats. Psychopharmacology. 2004;172(2):170–8.PubMedCrossRef
18.
Kuzmin A, Kreek MJ, Bakalkin G, Liljequist S. The nociceptin/orphanin FQ receptor agonist Ro 64-6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking. Neuropsychopharmacology. 2007;32(4):902–10.PubMedCrossRef
19.
Cruz MT, Herman MA, Kallupi M, Roberto M. Nociceptin/orphanin FQ blockade of corticotropin-releasing factor-induced gamma-aminobutyric acid release in central amygdala is enhanced after chronic ethanol exposure. Biol Psychiatry. 2012;71(8):666–76.PubMedCrossRef
20.
Tan YL, Sun H, Sun WJ, Zhang AH, Wang XJ. Research Progress of Chemistry and Pharmacology of Semen Ziziphi Spinosae. Lishizhen Medicine And Materia Medica Research. 2014;25(1):186–8.
21.
Shergis JL, Ni X, Sarris J, Zhang AL, Guo X, Xue CC, Lu C, Hugel H. Ziziphus spinosa seeds for insomnia: a review of chemistry and psychopharmacology. Phytomedicine. 2017;34:38–43.PubMedCrossRef
22.
Han H, Ma Y, Eun J, Hong J, Oh K. Anxiolytic-like effects of methanol extract of Zizyphi Spinosi semen in mice. Biomol Ther. 2007;15(3):175–81.CrossRef
23.
Han H, Ma Y, Eun JS, Li R, Hong JT, Lee MK, Oh KW. Anxiolytic-like effects of sanjoinine a isolated from Zizyphi Spinosi semen: possible involvement of GABAergic transmission. Pharmacol Biochem Behav. 2009;92(2):206–13.PubMedCrossRef
24.
Cao JX, Zhang QY, Cui SY, Cui XY, Zhang J, Zhang YH, Bai YJ, Zhao YY. Hypnotic effect of jujubosides from semen Ziziphi Spinosae. J Ethnopharmacol. 2010;130(1):163–6.PubMedCrossRef
25.
Wang Y, Huang M, Lu X, Wei R, Xu J. Ziziphi spinosae lily powder suspension in the treatment of depression-like behaviors in rats. BMC Complement Altern Med. 2017;17(1):238.PubMedPubMedCentralCrossRef
26.
Gu C, Zhao Z, Zhu X, Wu T, Lee BH, Jiao Y, Lee CW, Jung DH, Yang CH, Zhao R, Kim SC. Aqueous extract of semen Ziziphi Spinosae exerts anxiolytic effects during nicotine withdrawal via improvement of Amygdaloid CRF/CRF1R signaling. Evid Based Complement Alternat Med. 2018. https://​doi.​org/​10.​1155/​2018/​2419183.
27.
Kliethermes CL. Anxiety-like behaviors following chronic ethanol exposure. Neurosci Biobehav Rev. 2005;28(8):837–50.PubMedCrossRef
28.
Kim JH, Chung JY, Kwon YK, Kim KJ, Yang CH, Hahm DH, Lee HJ, Pyun KH, Shim I. Acupuncture reduces alcohol withdrawal syndrome and c-Fos expression in rat brain. Am J Chin Med. 2005;33(6):887–96.PubMedCrossRef
29.
Zhao RJ, Yoon SS, Lee BH, Kwon YK, Kim KJ, Shim I, Choi KH, Kim MR, Golden GT, Yang CH. Acupuncture normalizes the release of accumbal dopamine during the withdrawal period and after the ethanol challenge in chronic ethanol-treated rats. Neurosci Lett. 2006;395(1):28–32.PubMedCrossRef
30.
Zhao Z, Kim YW, Wu Y, Zhang J, Lee JH, Li X, Cho IJ, Park SM, Jung DH, Yang CH, Kim SC, Zhao R. Korean red ginseng attenuates anxiety-like behavior during ethanol withdrawal in rats. J Ginseng Res. 2014;38(4):256–63.PubMedPubMedCentralCrossRef
31.
Zhao Z, Kim SC, Zhao R, Wu Y, Zhang J, Liu H, Kim YW, Zhu X, Gu C, Lee CW, Lee BH, Jang EY, Ko HL, Yang CH. The tegmental-accumbal dopaminergic system mediates the anxiolytic effect of acupuncture during ethanol withdrawal. Neurosci Lett. 2015;597:143–8.PubMedCrossRef
32.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. San Diego: Academic Press; 1988.
33.
Adinoff B, Martin PR, Bone GH, Eckardt MJ, Roehrich L, George DT, Moss HB, Eskay R, Linnoila M, Gold PW. Hypothalamic-pituitary-adrenal axis functioning and cerebrospinal fluid corticotropin releasing hormone and corticotropin levels in alcoholics after recent and long-term abstinence. Arch Gen Psychiatry. 1990;47(4):325–30.PubMedCrossRef
34.
Reynolds AR, Saunders MA, Brewton HW, Winchester SR, Elgumati IS, Prendergast MA. Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist ORG 34517 reduces the severity of ethanol withdrawal and related hypothalamic-pituitary-adrenal axis activation. Drug Alcohol Depend. 2015;154:100–4.PubMedPubMedCentralCrossRef
35.
Zhao Z, Jin X, Wu Y, Yang X, Xu Y, Jiang JZ, Kim SC, Lee BH, Yang CH, R Z. Amygdaloid corticotropin-releasing factor is involved in the anxiolytic effect of acupuncture during ethanol withdrawal in rats. J Acupunct Meridian Stud. 2013;6(5):234–40.PubMedCrossRef
36.
Koob GF. Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry. 1999;46(9):1167–80.PubMedCrossRef
37.
Gilpin NW, Herman MA, Roberto M. The central amygdala as an integrative hub for anxiety and alcohol use disorders. Biol Psychiatry. 2015;77(10):859–69.PubMedCrossRef
38.
Walker CD, Toufexis DJ, Burlet A. Hypothalamic and limbic expression of CRF and vasopressin during lactation: implications for the control of ACTH secretion and stress hyporesponsiveness. Prog Brain Res. 2001;133:99–110.PubMedCrossRef
39.
Huang MM, Overstreet DH, Knapp DJ, Angel R, Wills TA, Navarro M, Rivier J, Vale W, Breese GR. Corticotropin-releasing factor (CRF) sensitization of ethanol withdrawal-induced anxiety-like behavior is brain site specific and mediated by CRF-1 receptors: relation to stress-induced sensitization. J Pharmacol Exp Ther. 2010;332(1):298–307.PubMedPubMedCentralCrossRef
40.
Yamano Y, Yoshioka M, Toda Y, Oshida Y, Chaki S, Hamamoto K, Morishima I. Regulation of CRF, POMC and MC4R gene expression after electrical foot shock stress in the rat amygdala and hypothalamus. J Vet Med Sci. 2004;66(11):1323–7.PubMedCrossRef
41.
42.
43.
Hauger RL, Risbrough V, Brauns O, Dautzenberg FM. Corticotropin releasing factor (CRF) receptor signaling in the central nervous system: new molecular targets. CNS Neurol Disord Drug Targets. 2006;5(4):453–79.PubMedPubMedCentralCrossRef
44.
Cipriano AC, Gomes KS, Nunes-de-Souza RL. CRF receptor type 1 (but not type 2) located within the amygdala plays a role in the modulation of anxiety in mice exposed to the elevated plus maze. Horm Behav. 2016;81:59–67.PubMedCrossRef
45.
Zhang Y, Simpson-Durand CD, Standifer KM. Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder. Br J Pharmacol. 2015;172(2):571–82.PubMedCrossRef
46.
Varty GB, Hyde LA, Hodgson RA, Lu SX, McCool MF, Kazdoba TM, Del Vecchio RA, Guthrie DH, Pond AJ, Grzelak ME, Xu X, Korfmacher WA, Tulshian D, Parker EM, Higgins GA. Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species. Psychopharmacology. 2005;182(1):132–43.PubMedCrossRef
47.
Witkin JM, Statnick MA, Rorick-Kehn LM, Pintar JE, Ansonoff M, Chen Y, Tucker RC, Ciccocioppo R. The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence. Pharmacol Ther. 2014;141(3):283–99.PubMedCrossRef
48.
Zhao Z, Kim SC, Wu Y, Zhang J, Xu Y, Cho IJ, Yang CH, Lee BH, Zhao R. Involvement of amygdaloid neuropeptide Y in the anxiolytic effects of acupuncture during ethanol withdrawal in rats. Neurosci Lett. 2014;567:19–23.PubMedCrossRef
49.
Ciccocioppo R, de Guglielmo G, Hansson AC, Ubaldi M, Kallupi M, Cruz MT, Oleata CS, Heilig M, Roberto M. Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors. J Neurosci. 2014;34(2):363–72.PubMedPubMedCentralCrossRef
50.
Aujla H, Cannarsa R, Romualdi P, Ciccocioppo R, Martin-Fardon R, Weiss F. Modification of anxiety-like behaviors by nociceptin/orphanin FQ (N/OFQ) and time-dependent changes in N/OFQ-NOP gene expression following ethanol withdrawal. Addict Biol. 2013;18(3):467–79.PubMedCrossRef
51.
Kallupi M, Varodayan FP, Oleata CS, Correia D, Luu G, Roberto M. Nociceptin/orphanin FQ decreases glutamate transmission and blocks ethanol-induced effects in the central amygdala of naive and ethanol-dependent rats. Neuropsychopharmacology. 2014;39(5):1081–92.PubMedCrossRef
52.
Leggett JD, Harbuz MS, Jessop DS, Fulford AJ. The nociceptin receptor antagonist [Nphe1,Arg14,Lys15]nociceptin/orphanin FQ-NH2 blocks the stimulatory effects of nociceptin/orphanin FQ on the HPA axis in rats. Neuroscience. 2006;141(4):2051–7.PubMedCrossRef
53.
Liu J, Zhai WM, Yang YX, Shi JL, Liu QT, Liu GL, Fang N, Li J, Guo JY. GABA and 5-HT systems are implicated in the anxiolytic-like effect of spinosin in mice. Pharmacol Biochem Behav. 2015;128:41–9.PubMedCrossRef
54.
de la Peña JB, Lee HL, Yoon SY, Kim GH, Lee YS, Cheong JH. The involvement of magnoflorine in the sedative and anxiolytic effects of Sinomeni caulis et Rhizoma in mice. J Nat Med. 2013;67(4):814–21.PubMedCrossRef
55.
Feng ZY, Guo DW, Su S, Zhao H, Zheng XX. Sedative and anticonvulsant effect of jujuboside A. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2002;31(2):103–6 Chinese.PubMed
56.
Ko SY, Lee HE, Park SJ, Jeon SJ, Kim B, Gao Q, Jang DS, Ryu JH. Spinosin, a C-Glucosylflavone, from Zizyphus jujuba var. spinosa ameliorates Aβ1-42 oligomer-induced memory impairment in mice. Biomol Ther (Seoul). 2015;23(2):156–64.CrossRef
57.
Liu Z, Zhao X, Liu B, Liu AJ, Li H, Mao X, Wu B, Bi KS, Jia Y. Jujuboside a, a neuroprotective agent from semen Ziziphi Spinosae ameliorates behavioral disorders of the dementia mouse model induced by Aβ 1-42. Eur J Pharmacol. 2014;738:206–13.PubMedCrossRef
Metadata
Title
Methanol extract of semen Ziziphi Spinosae attenuates ethanol withdrawal anxiety by improving neuropeptide signaling in the central amygdala
Authors
Li Bo Li
Young Woo Kim
Yu Hua Wang
Li Bai
Xiao Dong Zhu
Zheng Lin Zhao
Chul Won Lee
Yu Jiao
Tong Wu
Zhen Zhen Cai
Sang Chan Kim
Won G. An
Chae Ha Yang
Guang Cheng Cui
Rong Jie Zhao
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Anxiety
Published in
BMC Complementary Medicine and Therapies / Issue 1/2019
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-019-2546-0

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