This study examines the role of the cannabinoid CB2 receptor (CB2 r) on the vulnerability to ethanol consumption. The time-related and dose-response effects of ethanol on rectal temperature, handling-induced convulsions (HIC) and blood ethanol concentrations were evaluated in CB2 KO and wild-type (WT) mice. The reinforcing properties of ethanol were evaluated in conditioned place preference (CPP), preference and voluntary ethanol consumption and oral ethanol self-administration. Water-maintained behavior schedule was performed to evaluate the degree of motivation induced by a natural stimulus. Preference for non-alcohol tastants assay was performed to evaluate the differences in taste sensitivity. Tyrosine hydroxylase (TH) and μ-opioid receptor gene expressions were also measured in the ventral tegmental area and nucleus accumbens (NAcc), respectively. CB2 KO mice presented increased HIC score, ethanol-CPP, voluntary ethanol consumption and preference, acquisition of ethanol self-administration, and increased motivation to drink ethanol compared with WT mice. No differences were found between genotypes in the water-maintained behavior schedule or preference for non-alcohol tastants. Naïve CB2 KO mice presented increased μ-opioid receptor gene expression in NAcc. Acute ethanol administration (1-2 g/kg) increased TH and μ-opioid receptor gene expressions in CB2 KO mice, whereas the lower dose of ethanol decreased TH gene expression in WT mice. These results suggest that deletion of the CB2 r gene increased preference for and vulnerability to ethanol consumption, at least in part, by increased ethanol-induced sensitivity of the TH and μ-opioid receptor gene expressions in mesolimbic neurons. Future studies will determine the role of CB2 r as a target for the treatment of problems related with alcohol consumption.

This research was supported by ‘Instituto de Salud Carlos III’ (RETICS, RD06/0001/1004, RD12/0028/0019), ‘Plan Nacional Sobre Drogas’ (PNSD 2007/061; 2011/043), Fundación Sociosanitaria de Castilla—La Mancha, (FISCAM) and ‘Ministerio de Economía y Competitividad’ (#SAF 2008-01106, SAF 2011-23420) grants to J.M. Postdoctoral fellows A.O.A and A.T, and Raquel Poveda (R.P., technician) and Mar Ruiz (M.R., technician) are supported by FISCAM. F.N. (postdoctoral fellow), A.A.F. (postdoctoral fellow) and Analía Rico (A.R., technician) are supported by RETICS. MSGG (postdoctoral fellow) and Patricia Rodríguez (P.R., technician) are supported by Miguel Hernández University. We thank R.P., M.R., A.R and P.R. for excellent technical assistance. The partial support of FEDER funds (EU) is also acknowledged.

Peer reviewed