The role of the cannabinoid receptor 2 in alcohol-induced neuroinflammation and alcohol addiction

Abstract

Chronic alcohol abuse leads to severe brain damage, which has been associated with alcohol-induced neuroinflammation. Recently, the cannabinoid receptor 2 (CB₂), which is predominantly expressed on immune cells, has been shown to be involved in alcohol addiction. Therefore, this study aimed at investigating the role of the CB₂ in alcoholinduced neuroinflammation and at characterising alcohol-related behaviour in CB₂ knockout animals. First, the potency of different chronic alcohol models to induce neuroinflammation was analysed. To achieve this, levels of pro- and anti-inflammatory cytokines and glial activation markers were quantified in the cortex of the animals using ELISA and immuno-histochemical approaches. Next, we characterised the modulatory role of the CB₂ receptor in alcohol-induced neuroinflammation. We hypothesised that lack of CB₂ should be beneficial in alcohol-induced neuroinflammation. Therefore, the neuroinflammatory burden after chronic alcohol consumption was analysed in CB₂ deficient animals compared to WT controls. We can conclude that long-term models applied in this study led to neuroinflammation, as revealed by increased expression of pro-inflammatory cytokines. These changes were more pronounced when animals were continuously exposed to alcohol and additionally, we found a strong correlation between the duration of alcohol drinking and the severity of neuroinflammation. In line with this, long-term alcohol drinking led to a pro-inflammatory phenotype of microglia in the cortex. Furthermore, CB₂ deficiency dampens the inflammatory response in the cortex. However, this effect was strongly dependent on housing conditions. In a second approach, the alcohol drinking pattern of CB₂ deficient animals was analysed in different models that included environmental factors like social isolation, repeated withdrawal of alcohol or foot shock-induced stress. Finally, the development of tolerance, somatic signs of withdrawal and alcohol clearance were characterised in these mice. Interestingly, we detected that the CB₂ receptor increased alcohol drinking in a model for social drinking. Additionally, our data suggest that the CB₂ receptor modulates alcohol reward. Taken together, these data show that the CB₂ receptor is involved in a variety of alcohol-related phenotypes ranging from alcohol-induced neuroinflammation to alcohol reward. In addition, the function of this receptor is strongly modulated by the environment.