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Gene expression analyses of the opioid \u03bc receptor (<jats:italic>Oprm1<\/jats:italic>) in the nucleus accumbens (NAc), tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and the 5\u2010HT<jats:sub>1A<\/jats:sub> receptor in the dorsal raphe nucleus (DR) were carried out by real\u2010time PCR. The role of 5\u2010HT<jats:sub>1A<\/jats:sub> receptors in the ethanol reduction induced by the administration of CBD\u00a0+\u00a0naltrexone was analysed by using the 5\u2010HT<jats:sub>1A<\/jats:sub> receptor antagonist WAY100635 (0.3\u00a0mg\u00b7kg<jats:sup>\u22121<\/jats:sup>, i.p.).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The administration of CBD\u00a0+\u00a0naltrexone significantly reduced motivation and ethanol intake in the oral self\u2010administration procedure in a greater proportion than the drugs given alone. Only the combination of both drugs significantly reduced <jats:italic>Oprm1<\/jats:italic>, TH and 5\u2010HT<jats:sub>1A<\/jats:sub> gene expressions in the NAc, VTA and DR respectively. Interestingly, the administration of WAY100635 significantly blocked the actions of CBD\u00a0+\u00a0naltrexone but had no effects by itself.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The combination of low doses of CBD plus naltrexone were more effective than either CBD or naltrexone alone at reducing ethanol consumption and the motivation to drink. 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