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

摘要

Background: Emerging evidence suggests that the endocannabinoid system (ECS) is involved in modulating the rewarding effects of abused drugs. Recently, the cannabinoid receptor 2 (CB2R) was shown to be expressed in brain reward circuitry and is implicated in modulating the rewarding effects of alcohol. Methods: CB2 ligands and CB2R knockout (KO) mice were used to assess CB2R involvement in alcohol reward-related behavior in 2 well-established behavioral models: limited-access 2-bottle choice drinking and conditioned place preference (CPP). For the pharmacological studies, mice received pretreatments of either vehicle, the CB2R agonist JWH-133 (10 and 20 mg/kg) or the CB2R antagonist AM630 (10 and 20 mg/kg) 30 minutes before behavioral testing. For the genetic studies, CB2R KO mice were compared to wild-type (WT) littermate controls. Results: CB2R KO mice displayed increased magnitude of alcohol-induced CPP compared to WT mice. Neither agonism nor antagonism of CB2R affected alcohol intake or the expression of CPP, and antagonism of CB2R during CPP acquisition trials also did not affect CPP. Conclusions: The CB2R KO CPP data provide partial support for the hypothesis that CB2Rs are involved in the modulation of alcohol reward-related behaviors. However, pharmacological manipulation of CB2Rs did not alter alcohol's rewarding effects in the alcohol-seeking models used here. These results highlight the importance of pharmacological validation of effects seen with lifetime KO models. Given the ongoing efforts toward medications development, future studies should continue to explore the role of the CB2R as a potential neurobiological target for the treatment of alcohol use disorders.