Cannabidiol for the treatment of alcohol use disorder: Examination of potential receptor mechanisms in a murine model of binge-like alcohol consumption

Abstract

Binge drinking is a risky pattern of alcohol intake and a major predictor of alcohol use disorder (AUD). Current AUD medications have limited efficacy and poor patient compliance, calling for more effective therapeutics. Cannabidiol (CBD), a non-intoxicating component of cannabis, has emerged as a potential novel therapeutic based on preclinical evidence. However, potential receptor mechanisms involved in CBD’s alcohol-related effects have not been comprehensively investigated.

Using the murine drinking-in-the-dark model of binge drinking, the present research aimed to confirm a reduction of alcohol consumption with CBD (30, 60, 120 mg∙kg-1). Behavioural pharmacological approaches were used to explore the involvement of CBD interactions with previously identified target mechanisms, the serotonin 1A receptor (5-HT1AR) and peroxisome proliferator-activated receptor-gamma (PPARɣ), and two novel targets, the chemokine receptor type-4 (CXCR4) and neuropeptide S receptor (NPSR).

Acute CBD dose-dependently suppressed binge-like drinking and associated blood ethanol concentration. The effect was not driven by locomotor impairments and was maintained across sub-chronic treatment. Blockade of 5-HT1AR and PPARɣ had no impact on CBD’s reduction of alcohol consumption. Co-administration of subthreshold doses of CBD and a NPSR antagonist implicated NPSR blockade as a potential mechanism contributing to CBD’s effect on alcohol intake; whereas co-administration of CBD and a CXCR4 antagonist suggested CXCR4 was not involved. However, the selective CXCR4 antagonist, AMD3100, potently and dose-dependently reduced ethanol consumption.

CBD presents as a promising candidate to reduce voluntary alcohol consumption. Mechanisms driving CBD’s alcohol-related effects remain unclear and may involve polypharmacology, including actions at the NPSR identified in the present study. Establishing how CBD suppresses alcohol intake may facilitate the development of more targeted AUD therapeutics.