Badolato Connie J, Lynch Erin A, Arnold Jonathon C, McGregor Iain S, Bowen Michael T
Brain and Mind Centre, The University of Sydney, Camperdown, New South Wales, Australia.
Faculty of Science, School of Psychology, The University of Sydney, Camperdown, New South Wales, Australia.
Br J Pharmacol. 2025 Sep;182(18):4236-4261. doi: 10.1111/bph.70070. Epub 2025 May 27.
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.
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).
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.
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.
暴饮是一种危险的饮酒模式，也是酒精使用障碍（AUD）的主要预测指标。目前用于治疗AUD的药物疗效有限且患者依从性差，因此需要更有效的治疗方法。大麻二酚（CBD）是大麻中的一种无成瘾性成分，已成为一种潜在的新型治疗药物。然而，CBD与酒精相关作用的受体机制尚未得到全面研究。
我们利用小鼠黑暗中饮酒的暴饮模型，旨在证实CBD（7.5、15、30、60、120mg/kg）对雄性和雌性小鼠酒精摄入量的降低作用。采用行为药理学方法探讨CBD与已确定的靶机制（5-羟色胺-1A受体（5-HTR）和过氧化物酶体增殖物激活受体-γ（PPARɣ））以及新靶标趋化因子受体4型（CXCR4）和神经肽S受体（NPSR）的相互作用。
急性给予CBD可剂量依赖性地抑制暴饮样饮酒和血液乙醇浓度。该作用并非由运动障碍引起，且在亚慢性治疗期间持续存在。阻断5-HTR和PPARɣ对CBD降低酒精摄入量的作用没有影响。亚阈值剂量的CBD与NPSR拮抗剂共同给药表明，阻断NPSR是CBD发挥作用的潜在机制，而CBD与CXCR4拮抗剂共同给药则表明CXCR4不参与其中。然而，强效且选择性的CXCR4拮抗剂AMD3100可降低乙醇摄入量。
CBD是减少自愿饮酒的一个有前景的候选药物。驱动CBD与酒精相关作用的机制仍不清楚，可能涉及多药理学作用，包括本研究中确定的对NPSR的作用。
