Cannabinoid CB1 receptor in dopaminergic circuit from ventral tegmental area to nucleus accumbens links trait anxiety with reward learning

The endocannabinoid (eCB) system has risen as a critical modulator linking the environmental challenges to behavioral maladaptation, such as trait anxiety and reward learning impairment. However, the association between trait anxiety and reward learning and how they share molecular mechanism in eCB system is still unknown. Here, we utilized a series of behavioral tests to screen the correlation among the behavioral patterns, especially between trait anxiety and reward learning. The elevated platform stress and open field test (OFT) were employed to classify the mice into the different level of trait anxiety, and ethanol-induced conditioned place preference (CPP) was used to assess the ability of reward learning. Our results indicated that high trait anxiety (HTA) mice exhibited increased reward learning. Intracranial administration of the cannabinoid CB1 receptor (CB1R) antagonist AM-251 or agonist WIN55,212-2 in nucleus accumbens (NAc) showed the different effect on anxiety-like behavior and reward learning. Similarly, CB1R knockout in VTA dopaminergic (VTA^DA) neurons resulted in anxiety-like behavior and reward learning impairment. Thus, we reveal insight into the role of CB1R in dopaminergic circuit from VTA to NAc, and present the evidence for a shared molecular mechanism between anxiety and reward learning.