| Title | Brucine N-Oxide Reduces Ethanol Intake and Preference in Alcohol-Preferring Male Fawn-Hooded Rats |
| Authors | Wei, Shoupeng Li, Yu-ling Gong, Qi Liang, Hui Liu, Qing Bernardi, Rick E. Zhang, Han-Ting Chen, Feng Lawrence, Andrew J. Liang, Jian-hui |
| Affiliation | Peking Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing, Peoples R China Tongji Univ, Sch Med, East Hosp, Dept Pharm, Shanghai, Peoples R China Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany West Virginia Univ, Hlth Sci Ctr, Dept Behav Med & Psychiat, Morgantown, WV 26506 USA West Virginia Univ, Hlth Sci Ctr, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3010, Australia Peking Univ, Sch Pharmaceut Sci, Dept Mol & Cellular Pharmacol, Beijing 100191, Peoples R China |
| Keywords | NONENZYMATIC REDUCTION GLYCINE DRINKING ACAMPROSATE MECHANISMS STRYCHNINE CANCER METAANALYSIS ENHANCEMENT DEPRIVATION |
| Issue Date | May-2020 |
| Publisher | ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH |
| Abstract | Background Alcohol use disorder places a heavy burden on global public health systems and thus is in urgent need of improved pharmacotherapies. Previously, our group has demonstrated that 30 mg/kg of the indole alkaloid brucine significantly attenuates alcohol-drinking behavior; however, the high toxicity, poor water solubility, short half-life, and limited therapeutic window of brucine restrain its clinical application as an antialcoholism medication. We subsequently hypothesized that the oxide of brucine (brucine N-oxide) would produce a similar behavioral effect without the risk profile associated with brucine. Methods Male Fawn-Hooded rats with high innate alcohol preference underwent 2-bottle choice procedures (Experiments 1 to 3). Experiment 1 examined the effects of 7 daily BNO injections of 0, 30, 50, or 70 mg/kg (s.c.) on voluntary alcohol consumption (n = 9/group). Experiment 2 evaluated the impact of a single dose of 0 or 70 mg/kg BNO on the increased alcohol intake induced by a 4-day alcohol deprivation (n = 8/group). Experiment 3 tested the effect of 7 daily BNO injections of 0 or 70 mg/kg (s.c.) on sucrose preference (n = 6/group). Experiment 4 measured the median lethal dose (LD50) values of BNO and brucine to compare their acute toxicity in rats. Experiment 5 tested whether BNO (0, 30, 50, and 70 mg/kg, s.c.) affected locomotor activity using an open-field paradigm (n = 8/group). Finally, Experiment 6 evaluated the possible conditioned rewarding effects of 0, 30, 50, and 70 mg/kg BNO using the conditioned place preference paradigm (n = 6/group). Results BNO administration dose-dependently attenuated alcohol consumption without affecting food intake, total fluid consumption, or the natural preference for a sucrose solution, with 70 mg/kg BNO reducing consumption by 22.8%. A single dose of 70 mg/kg BNO significantly inhibited the alcohol deprivation effect. The LD50 values of BNO and brucine in rats were determined to be 1,103.5 +/- 177.0 mg/kg and 264.6 +/- 17.7 mg/kg, respectively. Finally, BNO administration did not affect spontaneous locomotor activity or induce a place preference. Conclusions BNO may help to control excessive alcohol use and should be considered a treatment strategy for future study and development. |
| URI | http://hdl.handle.net/20.500.11897/606886 |
| ISSN | 0145-6008 |
| DOI | 10.1111/acer.14344 |
| Indexed | SCI(E) Scopus |
| Appears in Collections: | 基础医学院 药学院 |
