Role of cannabinoid CB₂receptor in the reinforcing actions of ethanol

Abstract

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.

Genetic Versus Pharmacological Assessment of the Role of Cannabinoid Type 2 Receptors in Alcohol Reward‐Related Behaviors

“…However, the lack of a genotype effect is not consistent with a report by Ortega-Álvaro and colleagues (2015), who showed increased 24-hour drinking in CB2R KO mice compared to WT controls. One reason for these inconsistent findings could be related to the fact that the genetic background strain of the KO model in the Ortega-Álvaro and colleagues (2015) study was CD1 which are known to have low alcohol intake (Short et al, 2006). Another possibility is that CB2R KO mice have altered alcohol metabolism, but a recent study by Pradier and colleagues (2015) shows no difference in alcohol metabolism between genotypes.…”

“…A trend toward a Geno-type × Conditioning Subgroup interaction, F (1, 43) = 2.5, p = 0.1, was found; follow-up analyses showed a significant main effect of conditioning subgroup in KO mice only, F (1, 24) = 8.3, p < 0.01, similar to Ortega-Álvaro and colleagues (2015).…”

“…In addition, chronic treatment with a CB2R agonist and a CB2R antagonist enhanced and reduced alcohol consumption, respectively, in stressed but not control inbred mice (Ishiguro et al, 2007; Onaivi et al, 2008). CB2R KO mice consumed more alcohol in an unlimited-access 2-bottle choice study and developed more robust alcohol-induced CPP compared to WT littermate controls (Ortega-Álvaro et al, 2015). Also, CB2R activation, via the agonist β caryophyllene, reduced sensitivity to alcohol-induced sedation, alcohol intake, and alcohol-induced CPP in C57BL/6 mice (Al Mansouri et al, 2014).…”

“…We previously showed that HAP2 mice were more sensitive to pharmacological ECS manipulation compared to their low-alcohol-preferring counterparts (Powers et al, 2010), suggesting that genetic propensity toward high alcohol preference is associated with changes in ECS function. Second, we used mice with genetic deletion of CB2R (CB2R KO) to replicate the findings of Ortega-Álvaro and colleagues (2015) and to compare pharmacological versus genetic approaches in the study of the role of CB2R in alcohol reward-related behaviors. We hypothesized that pharmacological blockade and genetic deletion of CB2Rs would increase alcohol drinking and increase the expression of alcohol-induced CPP based on findings of Ortega-Álvaro and colleagues (2015), who showed that CB2R KO mice developed an alcohol-induced CPP, while WT controls did not.…”

“…Second, we used mice with genetic deletion of CB2R (CB2R KO) to replicate the findings of Ortega-Álvaro and colleagues (2015) and to compare pharmacological versus genetic approaches in the study of the role of CB2R in alcohol reward-related behaviors. We hypothesized that pharmacological blockade and genetic deletion of CB2Rs would increase alcohol drinking and increase the expression of alcohol-induced CPP based on findings of Ortega-Álvaro and colleagues (2015), who showed that CB2R KO mice developed an alcohol-induced CPP, while WT controls did not.…”