Cannabidiol dose dependently reduces alcohol intake in mice via a non-5-HT 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. However, receptor mechanisms in CBD's alcohol-related effects have not been investigated comprehensively.

EXPERIMENTAL APPROACH

Using the murine drinking-in-the-dark model of binge drinking, our research aimed to confirm a reduction of alcohol consumption with CBD (7.5, 15, 30, 60, 120 mg kg) in male and female mice. Behavioural pharmacological approaches were used to explore CBD interactions with identified target mechanisms: serotonin-1A receptor (5-HTR) and peroxisome proliferator-activated receptor-gamma (PPARɣ), and the novel targets, chemokine receptor type-4 (CXCR4) and neuropeptide S receptor (NPSR).

KEY RESULTS

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

CONCLUSIONS AND IMPLICATIONS

CBD represents 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.