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The endocannabinoid system plays a pivotal role in the regulation of ethanol reinforcing and motivational actions. The pharmacological manipulation of cannabinoid CB1 receptor (CB1r) in alcoholic patients provided discouraging results, so researchers have recently turned their attention to the cannabinoid CB2 receptor (CB2r). In this regard, the present study aims to characterise CB2r-mediated effects on ethanol self-administration and to describe the neurochemical mechanisms that may be involved. We performed an oral ethanol self-administration (OEA) experiment to analyse the effects of repeated administration of AM630 (1 mg kg-1, i.p.) or JWH133 (1 mg kg-1, i.p.) on the number of reinforced responses, the 8% ethanol intake and the breaking point values in male C57BL/6J mice. By means of real-time polymerase chain reaction (PCR), we also analysed relative gene expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA), and of mu-opioid receptor (OPRM1), CNR1 and CNR2 in the nucleus accumbens (NAcc). AM630-induced blockade of CB2r significantly increased the number of reinforced responses, 8% ethanol consumption and breaking point, whereas JWH133 treatment induced the opposite effect. Interestingly, the administration of AM630 significantly increased TH gene expression in the VTA, as well as OPRM1 and CNR1 gene expression in the NAcc, whereas administration with JWH133 decreased gene expression of these targets. In addition, CNR2 gene expression was unchanged with AM630 treatment but increased in animals treated with JWH133. The therapeutic implications of our results hold promise for CB2r as a means to manage alcohol use disorder and significantly contribute to improving understanding of the underlying neurobiological mechanisms involved., This research was supported by ‘Instituto de Salud Carlos III” (RTA, RD16/0017/0014, Fondos FEDER), ‘Plan Nacional sobre Drogas’ (PNSD, 2016/016) and ‘Ministerio de Economía y Competitividad’ (FIS, PI14/00438).