Genetic and pharmacological assessment of CB2 receptors in alcohol reward-related behaviors in mice

Emerging evidence suggests that the endocannabinoid system (ECS) is involved in modulating the rewarding effects of abused drugs, including alcohol. Recently, the cannabinoid receptor 2 (CB2) was shown to be expressed in brain reward circuitry and is implicated in modulating cocaine reward. The current study used both genetic and pharmacological techniques to assess CB2 involvement in alcohol reward-related behavior using two well-established models: limited-access two-bottle choice drinking and conditioned place preference (CPP). For the pharmacological studies, male and female mice selectively bred for high alcohol preference (HAP2) were used because they drink pharmacologically relevant amounts of alcohol, readily acquire alcohol-induced CPP, and show increased sensitivity to pharmacological manipulations of the ECS. Mice received pretreatments of either vehicle, the CB2 agonist JWH-133 (10 and 20 mg/kg), or the CB2 antagonist AM630 (10 and 20 mg/kg) 30 min before behavioral testing. For the genetic studies, CB2 knockout (KO) mice were compared to wild type (WT) littermate controls. For the drinking studies, mice received 3 days of habituation to saline injections in the home cage followed by 4 days of water/saccharin and alcohol/saccharin access without injections. On the 8th day mice received drug pretreatments. For the CPP study, mice were given a pretest, 4 conditioning trials, and two CPP tests separated by 24 hrs. Mice received drug pretreatments prior to the first test and saline prior to the second test in order to assess drug effects on the expression of CPP and to see if any treatment effects persisted in the absence of drug. CB2 KO mice displayed increased magnitude of alcohol-induced CPP compared to WT mice. Pharmacological manipulations of CB2 did not affect CPP, but the 20 mg/kg dose of the CB2 agonist increased alcohol intake. Given that CB2 agonism has been shown to reduce cocaine self-administration in mice, and that CB2 KO mice show increased magnitude of alcohol-induced CPP compared to WT mice, increased alcohol intake following CB2 activation may reflect decreased sensitivity to alcohol reward, leading to increased alcohol consumption by HAP2 mice to achieve the same pharmacological effect. That pharmacological manipulations of CB2 did not affect the expression of CPP suggests that CB2 may not be involved in the expression of conditioned alcohol reward; rather, CB2 may be important in regulating the primary rewarding effects of alcohol