# Synergistic Effect of Combination Treatment of Brexpiprazole and Nalmefene on Ethanol Intake in Rats

## TL;DR

This study shows that combining two drugs, brexpiprazole and nalmefene, can significantly reduce alcohol intake in rats more effectively than either drug alone.

## Contribution

The novel finding is the synergistic effect of subeffective doses of brexpiprazole and nalmefene in reducing ethanol intake in rats.

## Key findings

- Brexpiprazole (0.1 mg/kg) and nalmefene (0.4 mg/kg) alone significantly decreased ethanol intake in rats.
- The combination of subeffective doses of brexpiprazole (0.01 mg/kg) and nalmefene (0.04 mg/kg) synergistically reduced ethanol intake.
- The combination effect was statistically significant (p = 0.0033) compared to pre-treatment levels.

## Abstract

Reduction of alcohol consumption is one of treatment goals to reduce harm among individuals with alcohol use disorder (AUD), a major worldwide health problem, for which nalmefene, an opioid receptor modulator, is used. In this study, the effect of nalmefene on ethanol (EtOH) intake, already reported, was evaluated in Wistar rats, as validation. In addition, effects of brexpiprazole, serotonin–dopamine activity modulator, alone and in combination with nalmefene were evaluated to investigate further treatment option for AUD.

During the first training phase, animals had 10% EtOH as the only drinking fluid available for the first 5 days. Then, the animals had a 24‐h free choice between EtOH and water for 39 days which is named the continual access paradigm. Thereafter, the limited access paradigm, which restricted the availability of 10% EtOH to 1 h every day, was carried out for 114 days. EtOH intake (g/kg/1 h) was determined by weighing 10% EtOH bottles before and after the limited EtOH access every day. Brexpiprazole (0.01–0.1 mg/kg, orally) and nalmefene (0.04–0.4 mg/kg, subcutaneously) were daily administered to rats 1 h or 20 min before starting the limited access paradigm for consecutive 4 days, respectively. The combination effect was evaluated using each subeffective dose of brexpiprazole and nalmefene which did not significantly reduce EtOH intake. The daily and the average EtOH intake for 4 days before and during the treatment with test compounds were statistically analyzed.

Brexpiprazole (0.1 mg/kg) and nalmefene (0.4 mg/kg) alone significantly decreased EtOH intake. Moreover, the combination of subeffective doses of brexpiprazole (0.01 mg/kg) and nalmefene (0.04 mg/kg) significantly and synergistically decreased EtOH intake.

These data suggest that brexpiprazole may have the potential to decrease alcohol intake in AUD patients. In addition, brexpiprazole may have a synergistic therapeutic effect with nalmefene in those patients.

Combination effect of nalmefene and brexpiprazole on ethanol intake in rats. The combination of subeffective doses of nalmefene (0.04 mg/kg, s.c.) and brexpiprazole (0.01 mg/kg, p.o.) significantly and synergistically decreased the average ethanol intake for 4 days compared with before the treatment (interaction effect: p = 0.0033 by two‐way ANOVA).