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Cannabidiol (CBD), a non\u2010intoxicating component of cannabis, has emerged as a potential novel therapeutic. However, receptor mechanisms in CBD's alcohol\u2010related effects have not been investigated comprehensively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Using the murine drinking\u2010in\u2010the\u2010dark model of binge drinking, our research aimed to confirm a reduction of alcohol consumption with CBD (7.5, 15, 30, 60, 120\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>) in male and female mice. Behavioural pharmacological approaches were used to explore CBD interactions with identified target mechanisms: serotonin\u20101A receptor (5\u2010HT<jats:sub>1A<\/jats:sub>R) and peroxisome proliferator\u2010activated receptor\u2010gamma (PPAR\u0263), and the novel targets, chemokine receptor type\u20104 (CXCR4) and neuropeptide S receptor (NPSR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Acute CBD dose dependently suppressed binge\u2010like drinking and blood ethanol concentration. The effect was not driven by locomotor impairments and was maintained across sub\u2010chronic treatment. Blockade of 5\u2010HT<jats:sub>1A<\/jats:sub>R and PPAR\u0263 had no impact on CBD's reduction of alcohol consumption. Co\u2010administration of subthreshold CBD doses and a NPSR antagonist implicated NPSR blockade as a potential mechanism contributing to CBD's effect, whereas co\u2010administration of CBD and a CXCR4 antagonist suggested CXCR4 was not involved. However, the potent and selective CXCR4 antagonist AMD3100 reduced ethanol consumption.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>CBD represents a promising candidate to reduce voluntary alcohol consumption. Mechanisms driving CBD's alcohol\u2010related effects remain unclear and may involve polypharmacology, including actions at the NPSR identified in the present study.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70070","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T02:17:06Z","timestamp":1748398626000},"page":"4236-4261","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cannabidiol dose dependently reduces alcohol intake in mice via a non\u20105\u2010HT<sub>1A<\/sub> receptor mechanism: Exploration of other potential receptor targets"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-0044","authenticated-orcid":false,"given":"Connie J.","family":"Badolato","sequence":"first","affiliation":[{"name":"Brain and Mind Centre The University of Sydney  Camperdown New South Wales Australia"},{"name":"Faculty of Science, School of Psychology The 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