Significant progress was made on this research project during this reporting period. We have recently reported that functional CB2Rs are expressed in the brain and functionally modulate dopamine neuron activity and cocaine self-administration. However, this finding is disputed because of the specificity of CB2R antibody signals. In our recent publication authored by Zhang et al (2018), we used two strains of currently available partial CB2-knockout (CB2-KO) mice as controls, four anti-rat or anti-mouse CB2R antibodies, and mRNA quantification to further address this issue. We found that none of the tested four polyclonal antibodies are highly mouse CB2R-specific. The presence of non-specific binding may be related to the expression of mutant or truncated CB2R-like proteins in partial CB2-KO mice and the use of anti-rat CB2 antibodies since the epitopes are different between rat and mouse CB2Rs. In addition, we also generated conditional CB2-knocked mice as controls, in which CB2R gene is deleted only in midbrain DA neurons (by Liu et al., 2018), we found that the deletion of CB2Rs in DA neurons significantly enhances motor activities and cocaine-enhanced CPP, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. These findings provide additional evidence supporting the presence of endogenous CB2Rs in midbrain DA neurons and suggest that the endogenous CB2Rs in DA neurons play an important role in the modulation of reward, psychomotor behaviors, anxiety, depression, and pain sensation. In the paper authored by He et al (2018), we further explored the potential use of a novel neutral CB1R antagonist (AM4113) in medication development for the treatment of opioid addiction. In this study, we found that the neutral CB1R antagonist AM4113 retains the therapeutic anti-addictive effects of the prototypic CB1R antagonist/partial agonist, SR141716A, in nicotine and opioid self-administration models but has fewer unwanted side effects as assessed by electrical brain-stimulation reward. These findings suggest that neutral CB1R antagonists such as AM4113 deserve further research as a new class of CB1R-based medications for the treatment of nicotine or opioid addiction without SR141716A-like aversive effects.
