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

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 Noxide) 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 AE 177.0 mg/kg and 264.6 AE 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. are contribute equally to this work.

Molecular chaperone heat shock protein 70 inhibitors suppress conditioned place preference induced by morphine exposure in male rats

“…CPP is a model used to study the conditioned reinforcing properties of drugs of abuse through the association of putative drug reward with neutral environment cues. 6,18 In this study, we investigated the role of Hsp70 in morphine CPP in male rats using the pharmacological interventions. In this study, we found that icv PES and KNK437 4) In their study, mice were treated with GGA (800 mg/kg/day) in an oral manner, whereas in our study, rats were injected with the pharmacological antagonists/inhibitors in an icv way.…”

“…CPP is a model used to study the conditioned reinforcing properties of drugs of abuse through the association of putative drug reward with neutral environment cues 6,18 . In this study, we investigated the role of Hsp70 in morphine CPP in male rats using the pharmacological interventions.…”

“…In this study, we examined the effects of the functional Hsp70 inhibitors Pifithrin‐μ (PES) and methylene blue (MB) and the transcriptional inhibitor N ‐formyl‐3,4‐methylenedioxybenzylidine‐γ‐butyrolactam (KNK437) on the development and expression of morphine CPP. Furthermore, we measured the expression levels of Hsp70 in the mPFC, VTA, NAc shell and core following KNK437 administered during the development and expression of morphine CPP 15–18 . Thus, we have further elucidated the function of Hsp70 within the mesocorticolimbic system in morphine‐induced rewarding effect in male rats.…”

“…Furthermore, we measured the expression levels of Hsp70 in the mPFC, VTA, NAc shell and core following KNK437 administered during the development and expression of morphine CPP. [15][16][17][18] Thus, we have further elucidated the function of Hsp70 within the mesocorticolimbic system in morphine-induced rewarding effect in male rats.…”

Variations of Brain Functional Connectivity in Alcohol-Preferring and Non-Preferring Rats with Consecutive Alcohol Training or Acute Alcohol Administration

“…Single-housed P- and NP-rats (male, ~200 g) had continuous access to one bottle of 5% alcohol ( v / v ) and one bottle of water in their home cage for four consecutive weeks according to a two-bottle free choice (2-BC) paradigm [ 23 , 24 ]. The mass of drinking liquid (5% alcohol and water) was monitored every day, and the bottles were randomly replaced every day.…”