Cannabidiol dose-dependently reduces alcohol intake in mice via a non-5-HT1A receptor mechanism: Exploration of other potential receptor targets

Background and Purpose: 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. Experimental Approach: Using the murine drinking-in-the-dark model of binge drinking, the present research aimed to confirm a reduction of alcohol consumption with CBD (7.5, 15, 30, 60, 120 mg∙kg-1) in male and female mice. Behavioural pharmacological approaches were used to explore 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). Key Results: 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 potent and selective CXCR4 antagonist AMD3100 dose-dependently reduced ethanol consumption. Conclusion and Implications: CBD presents 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.