Aticaprant (Clinically Developed Kappa-Opioid Receptor Antagonist) Combined With Naltrexone Prevents Alcohol...

Area of Science:

• Neuroscience
• Pharmacology
• Addiction Medicine

Background:

• Alcohol dependence is a major health issue with relapse as a key treatment target.
• Aticaprant, a kappa-opioid receptor (KOR) antagonist, is being developed for depression and anhedonia, and has shown potential in reducing alcohol intake and seeking in rodents.
• The alcohol deprivation effect (ADE) paradigm in mice is used to model alcohol relapse episodes in humans.

Purpose of the Study:

• To investigate the effects of aticaprant, alone and in combination with naltrexone, on alcohol relapse-like drinking using the mouse ADE paradigm.
• To compare the efficacy of aticaprant with a long-acting KOR antagonist, nor-BNI, in the ADE model.
• To assess potential synergistic effects and tolerance development with the aticaprant and naltrexone combination.

Main Methods:

• Mice underwent intermittent-access alcohol drinking followed by a 1-week abstinence period to induce the ADE.
• Aticaprant (0.3-3 mg/kg) and/or naltrexone (1 mg/kg) were administered to mice during the abstinence period.
• Nor-BNI, a long-acting KOR antagonist, was used as a reference compound.
• Alcohol intake and ADE were measured to assess drug efficacy.

Main Results:

• Aticaprant alone dose-dependently decreased alcohol ADE in both male and female mice.
• A combination of a low dose of aticaprant (0.3 mg/kg) and naltrexone (1 mg/kg) significantly reduced ADE in both sexes.
• The combination therapy showed synergistic effects, with efficacy maintained after a multi-dosing regimen without tolerance development.
• Nor-BNI, alone or with naltrexone, did not affect the ADE.

Conclusions:

• Short-acting KOR antagonist aticaprant shows efficacy in reducing alcohol relapse-like behavior.
• A combination of aticaprant and low-dose naltrexone exhibits synergistic effects and therapeutic potential for alcohol relapse treatment.
• This combination may offer a novel strategy for managing alcohol dependence, particularly in preventing relapse.