Brucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats
Abstract
Yu-ling LI1, Qing LIU1, Qi GONG1, Jun-xu LI2, Shou-peng WEI1, Yan-ting WANG1, Hui LIANG1, Min ZHANG1, Li JING2, Zheng YONG3, Andrew J LAWRENCE4, *, Jian-hui LIANG1, *
1National Institute on Drug Dependence, Peking University, Beijing 100191, China; 2Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA; 3Institute of Pharmacology & Toxicology, Academy of Military Medical Sciences, Beijing 100850, China; 4Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia
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.
Keywords: alcoholism; ethanol; brucine; glycine receptor antagonist; Fawn-Hooded (FH/Wjd) rat
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.
Part of the results have been published as meeting abstract in Acta Pharmacol Sin 2013; 34: s129 and Chin Pharmacol 2013; 13: 18–9.
* To whom correspondence should be addressed.
E-mail liangjh@bjmu.edu.cn (Jian-hui LIANG);
andrew.lawrence@florey.edu.au (Andrew J LAWRENCE)
Received 2014-01-01 Accepted 2014-03-05
Keywords:
1National Institute on Drug Dependence, Peking University, Beijing 100191, China; 2Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA; 3Institute of Pharmacology & Toxicology, Academy of Military Medical Sciences, Beijing 100850, China; 4Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia
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.
Keywords: alcoholism; ethanol; brucine; glycine receptor antagonist; Fawn-Hooded (FH/Wjd) rat
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.
Part of the results have been published as meeting abstract in Acta Pharmacol Sin 2013; 34: s129 and Chin Pharmacol 2013; 13: 18–9.
* To whom correspondence should be addressed.
E-mail liangjh@bjmu.edu.cn (Jian-hui LIANG);
andrew.lawrence@florey.edu.au (Andrew J LAWRENCE)
Received 2014-01-01 Accepted 2014-03-05