Brucine N‐Oxide Reduces Ethanol Intake and Preference in Alcohol‐Preferring Male Fawn‐Hooded Rats. (17th May 2020) - Wei, Shoupeng
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. Abstract : Brucine N‐oxide (BNO) treatment at 30, 50 and 70 mg/kg (7 d, s.c., bid) dose‐dependently attenuated ethanol intake (A) and preference (B) in alcohol‐preferring male FH/Wjd rats, without disturbing the water (C) and food (D) consumption. BNO may help to control excessive alcohol use and should be considered as a novel treatment strategy for alcoholism.