Increased cocaine motivation in tree shrews is modulated by striatal dopamine D1 receptor-mediated upregulation of Ca_v1.2

The progressively increased motivation for cocaine during abstinence is closely associated with the dysfunction of dopamine (DA) system. As DA receptors also dynamically regulate L-type calcium channels (LTCCs), in this study we examined how DA receptors (D1R or D2R) and LTCCs (Ca_v1.2 or Ca_v1.3) exert their influences on cocaine-seeking in a tree shrew (Tupaia belangeri chinensis) model. First, we demonstrated the ‘incubation’ effect by showing tree shrews exhibited a significantly higher seeking behaviour on withdrawal day (WD) 45 than on WD1. Then, we confirmed that longer abstinence period induced higher D1R expression in the nucleus accumbens (NAc). Next, we showed that LTCCs in the NAc participated in drug seeking. Moreover, Ca_v1.2 expression in the NAc was increased on WD45, and disruption of the Ca_v1.2 inhibited drug seeking. Finally, we found that D1R antagonist blocked the increase of Ca_v1.2 on drug-seeking test. Collectively, these findings suggest that D1R-mediated upregulation of Ca_v1.2 is involved in the incubation of cocaine craving.