Brucine N-Oxide Reduces Ethanol Intake and Preference in Alcohol-Preferring Male Fawn-Hooded Rats.

Abstract

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. 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). 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. BNO may help to control excessive alcohol use and should be considered a treatment strategy for future study and development.