Abstract
Aim:
Brucine (BRU) extracted from the seeds of Strychnos nux-vomica L is glycine receptor antagonist. We hypothesize that BRU may modify alcohol consumption by acting at glycine receptors, and evaluated the pharmacodynamic profiles and adverse effects of BRU in rat models of alcohol abuse.
Methods:
Alcohol-preferring Fawn-Hooded (FH/Wjd) rats were administered BRU (10, 20 or 30 mg/kg, sc). The effects of BRU on alcohol consumption were examined in ethanol 2-bottle-choice drinking paradigm, ethanol/sucrose operant self-administration paradigm and 5-d ethanol deprivation test. In addition, open field test was used to assess the general locomotor activity of FH/Wjd rats, and conditioned place preference (CPP) was conducted to assess conditioned reinforcing effect.
Results:
In ethanol 2-bottle-choice drinking paradigm, treatment with BRU for 10 consecutive days dose-dependently decreased the ethanol intake associated with a compensatory increase of water intake, but unchanged the daily total fluid intake and body weight. In ethanol/sucrose operant self-administration paradigms, BRU (30 mg/kg) administered before each testing session significantly decreased the number of lever presses for ethanol and the ethanol intake, without affecting the number of sucrose (10%) responses, total sucrose intake, and the number of lever presses for water. Acute treatment with BRU (30 mg/kg) completely suppressed the deprivation-induced elevation of ethanol consumption. Treatment with BRU (10, 20, and 30 mg/kg) did not alter locomotion of FH/Wjd rats, nor did it produce place preference or aversion.
Conclusion:
BRU selectively decreases ethanol consumption with minimal adverse effects. Therefore, BRU may represent a new pharmacotherapy for alcoholism.
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References
Jupp B, Lawrence AJ . New horizons for therapeutics in drug and alcohol abuse. Pharmacol Ther 2010; 125: 138–68.
Liu Q, Lawrence AJ, Liang JH . Traditional Chinese medicine for treatment of alcoholism: from ancient to modern. Am J Chin Med 2011; 39: 1–13.
Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, et al. Carcinogenicity of alcoholic beverages. Lancet Oncol 2007; 8: 292–3.
Roerecke M, Rehm J . Ischemic heart disease mortality and morbidity rates in former drinkers: a meta-analysis. Am J Epidemiol 2011; 173: 245–58.
Samokhvalov AV, Irving H, Mohapatra S, Rehm J . Alcohol consumption, unprovoked seizures, and epilepsy: a systematic review and meta-analysis. Epilepsia 2010; 51: 1177–84.
Spicak J, Pulkertova A, Kralova-Lesna I, Suchanek P, Vitaskova M, Adamkova V . Alcoholic chronic pancreatitis and liver cirrhosis: coincidence and differences in lifestyle. Pancreatology 2012; 12: 311–6.
Krampe H, Stawicki S, Wagner T, Bartels C, Aust C, Rüther E, et al. Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome. Alcohol Clin Exp Res 2006; 30: 86–95.
Kampman KM, Pettinati HM, Lynch KG, Xie H, Dackis C, Oslin DW, et al. Initiating acamprosate within-detoxification versus post-detoxification in the treatment of alcohol dependence. Addict Behav 2009; 34: 581–6.
O'Brien CP, Volpicelli LA, Volpicelli JR . Naltrexone in the treatment of alcoholism: a clinical review. Alcohol 1996; 13: 35–9.
Rösner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M . Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2010; (12): CD001867.
Heilig M, Egli M . Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 2006; 111: 855–76.
Yin W, Wang TS, Yin FZ, Cai BC . Analgesic and anti-inflammatory properties of brucine and brucine N-oxide extracted from seeds of Strychnos nux-vomica. J Ethnopharmacol 2003; 88: 205–14.
Chen J, Hu W, Qu YQ, Dong J, Gu W, Gao Y, et al. Evaluation of the pharmacodynamics and pharmacokinetics of brucine following transdermal administration. Fitoterapia 2013; 86: 193–201.
Deng XK, Yin W, Li WD, Yin FZ, Lu XY, Zhang XC, et al. The anti-tumor effects of alkaloids from the seeds of Strychnos nux-vomica on HepG2 cells and its possible mechanism. J Ethnopharmacol 2006; 106: 179–86.
Yang BC, Chu ZF, Zhu S, Wang LJ, Feng YH, Li FH, et al. Study of pharmacokinetics and tissue distribution of liposomal brucine for dermal administration. Int J Nanomed 2011; 6: 1109–16.
Chen J, Hou T, Fang Y, Chen ZP, Liu X, Cai H, et al. HPLC determination of strychnine and brucine in rat tissues and the distribution study of processed semen strychni. Yakugaku Zasshi 2011; 131: 721–9.
Dhalwal K, Shinde VM, Namdeo AG, Mahadik KR, Kadam SS . Development and validation of a TLC-densitometric method for the simultaneous quantitation of strychnine and brucine from Strychnos spp. and its formulations. J Chromatogr Sci 2007; 45: 706–9.
Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, et al. Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors. Nature 1997; 389: 385–9.
Mascia MP, Machu TK, Harris RA . Enhancement of homomeric glycine receptor function by long-chain alcohols and anaesthetics. Br J Pharmacol 1996; 119: 1331–6.
Jensen AA, Gharagozloo P, Birdsall NJ, Zlotos DP . Pharmacological characterisation of strychnine and brucine analogues at glycine and alpha7 nicotinic acetylcholine receptors. Eur J Pharmacol 2006; 539: 27–33.
Overstreet DH, McArthur RA, Rezvani AH, Post C . Selective inhibition of alcohol intake in diverse alcohol-preferring rat strains by the 5-HT2A antagonists amperozide and FG 5974. Alcohol Clin Exp Res 1997; 21: 1448–54.
Jing L, Zhang ZH, Wang WP, Zhang M, Luo J, Chen F, et al. Characteristics of alcohol-preferring behavior in FH/Wjd rats. Chin J Pharmacol Toxicol 2009; 23: 65–9.
Wen RT, Zhang M, Qin WJ, Liu Q, Wang WP, Lawrence AJ, et al. The phosphodiesterase-4 (PDE4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring Fawn-Hooded rats. Alcohol Clin Exp Res 2012; 36: 2157–67.
Samson HH . Initiation of ethanol reinforcement using a sucrose-substitution procedure in food- and water-sated rats. Alcohol Clin Exp Res 1986; 10: 436–42.
Steensland P, Simms JA, Holgate J, Richards JK, Bartlett SE . Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking. Proc Natl Acad Sci U S A 2007; 104: 12518–23.
Arolfo MP, Yao L, Gordon AS, Diamond I, Janak PH . Ethanol operant self-administration in rats is regulated by adenosine A2 receptors. Alcohol Clin Exp Res 2004; 28: 1308–16.
Rezvani AH, Parsian A, Overstreet DH . The Fawn-Hooded (FH/Wjd) rat: a genetic animal model of comorbid depression and alcoholism. Psychiatr Genet 2002; 12: 1–16.
Arolfo MP, Overstreet DH, Yao L, Fan P, Lawrence AJ, Tao G, et al. Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. Alcohol Clin Exp Res 2009; 33: 1935–44.
Liu Q, Zhang M, Qin WJ, Wang YT, Li YL, Jing L, et al. Septal nuclei critically mediate the development of behavioral sensitization to a single morphine injection in rats. Brain Res 2012; 1454: 90–9.
Hu W, Lu T, Chen A, Huang Y, Hansen R, Chandler LJ, et al. Inhibition of phosphodiesterase-4 decreases ethanol intake in mice. Psychopharmacology (Berl) 2011; 218: 331–9.
Zhang M, Jing L, Liu Q, Wen RT, Li JX, Li YL, et al. Tramadol induces conditioned place preference in rats: interactions with morphine and buprenorphine. Neurosci Lett 2012; 520: 87–91.
dela Cruz AM, Herin DV, Grady JJ, Cunningham KA . Novel approach to data analysis in cocaine-conditioned place preference. Behav Pharmacol 2009; 20: 720–30.
Rezvani AH, Overstreet DH, Janowsky DS . Genetic serotonin deficiency and alcohol preference in the fawn hooded rats. Alcohol Alcohol 1990; 25: 573–5.
Rodd ZA, Bell RL, Sable HJ, Murphy JM, McBride WJ . Recent advances in animal models of alcohol craving and relapse. Pharmacol Biochem Behav 2004; 79: 439–50.
Cowen MS, Rezvani AH, Jarrott B, Lawrence AJ . Ethanol consumption by Fawn-Hooded rats following abstinence: effect of naltrexone and changes in mu-opioid receptor density. Alcohol Clin Exp Res 1999; 23: 1008–14.
Cowen MS, Adams C, Kraehenbuehl T, Vengeliene V, Lawrence AJ . The acute anti-craving effect of acamprosate in alcohol-preferring rats is associated with modulation of the mesolimbic dopamine system. Addict Biol 2005; 10: 233–42.
Overstreet DH, Rezvani AH, Djouma E, Parsian A, Lawrence AJ . Depressive-like behavior and high alcohol drinking co-occur in the FH/WJD rat but appear to be under independent genetic control. Neurosci Biobehav Rev 2007; 31: 103–14.
Carroll ME, Morgan AD, Anker JJ, Perry JL, Dess NK . Selective breeding for differential saccharin intake as an animal model of drug abuse. Behav Pharmacol 2008; 19: 435–60.
McBride WJ, Le AD, Noronha A . Central nervous system mechanisms in alcohol relapse. Alcohol Clin Exp Res 2002; 26: 280–6.
Spanagel R, Hölter SM, Allingham K, Landgraf R, Zieglgänsberger W . Acamprosate and alcohol: I. Effects on alcohol intake following alcohol deprivation in the rat. Eur J Pharmacol 1996; 305: 39–44.
Mucha RF, Iversen SD . Reinforcing properties of morphine and naloxone revealed by conditioned place preferences: a procedural examination. Psychopharmacology (Berl) 1984; 82: 241–7.
Aguayo LG, Pancetti FC . Ethanol modulation of the gamma- aminobutyric acidA- and glycine-activated Cl− current in cultured mouse neurons. J Pharmacol Exp Ther 1994; 270: 61–9.
Welsh BT, Goldstein BE, Mihic SJ . Single-channel analysis of ethanol enhancement of glycine receptor function. J Pharmacol Exp Ther 2009; 330: 198–205.
Engblom AC, Akerman KE . Effect of ethanol on gamma-aminobutyric acid and glycine receptor-coupled Cl− fluxes in rat brain synaptoneurosomes. J Neurochem 1991; 57: 384–90.
Jonsson S, Kerekes N, Hyytiä P, Ericson M, Söderpalm B . Glycine receptor expression in the forebrain of male AA/ANA rats. Brain Res 2009; 1305:S27–36.
Li J, Nie H, Bian W, Dave V, Janak PH, Ye JH . Microinjection of glycine into the ventral tegmental area selectively decreases ethanol consumption. J Pharmacol Exp Ther 2012; 341: 196–204.
Molander A, Löf E, Stomberg R, Ericson M, Söderpalm B . Involvement of accumbal glycine receptors in the regulation of voluntary ethanol intake in the rat. Alcohol Clin Exp Res 2005; 29: 38–45.
Rodd-Henricks ZA, McKinzie DL, Edmundson VE, Dagon CL, Murphy JM, McBride WJ, et al. Effects of 5-HT3 receptor antagonists on daily alcohol intake under acquisition, maintenance, and relapse conditions in alcohol-preferring (P) rats. Alcohol 2000; 21: 73–85.
Rezvani AH, Overstreet DH, Janowsky DS . Drug-induced reductions in ethanol intake in alcohol preferring and Fawn-Hooded rats. Alcohol Alcohol Suppl 1991; 1: 433–7.
Zlotos DP, Buller S, Stiefl N, Baumann K, Mohr K . Probing the pharmacophore for allosteric ligands of muscarinic M2 receptors: SAR and QSAR studies in a series of bisquaternary salts of caracurine V and related ring systems. J Med Chem 2004; 47: 3561–71.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (30870894 and 81373390); National Basic Research Program of China (2009CB522000); National Key Technology R&D Program of China (2011BAK04B08); and Key Research Items of Ministry of Public Security (2009ZDYJHLJT003). Jian-hui LIANG was supported by the National Institute on Drug Abuse at the National Institutes of Health under awards (R01DA034806 and R21DA033426). Andrew J LAWRENCE is a Principal Research Fellow at the NHMRC, Australia, and was supported by the Victorian Government's Operational Infrastructure Support Scheme.
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Part of the results have been published as meeting abstract in Acta Pharmacol Sin 2013; 34: s129 and Chin Pharmacol 2013; 13: 18–9.
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Li, Yl., Liu, Q., Gong, Q. et al. Brucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats. Acta Pharmacol Sin 35, 853–861 (2014). https://doi.org/10.1038/aps.2014.28
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DOI: https://doi.org/10.1038/aps.2014.28
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