Alterations of Dopamine Receptors and the Adaptive Changes of L-Type Calcium Channel Subtypes Regulate Cocaine-Seeking Habit in Tree Shrew.

The putamen (Put) is necessary for habitual actions, while the nucleus caudate (Cd) is critical for goal-directed actions. However, compared with the natural reward (such as sucrose)-seeking habit, how drug-related dysfunction or imbalance between the Put and Cd is involved in cocaine-seeking habit, which is not easy to bias behavior to goal-directed actions, is absent. Therefore, in our present study, in comparison with sucrose-habitual behavior, we evaluated the distinctive changes of the two subtypes of dopamine (DA) receptors (D1R and D2R) in cocaine-seeking habitual behavior animals. Moreover, the adaptive changes of Ca v 1.2 and Ca v 1.3, as prime downstream targets of D1R and D2R respectively, were also assessed. Our results showed that a similar percentage of the animals exhibited habitual seeking behavior after cocaine or sucrose variable-interval self-administration (SA) training in tree shrews. In addition, compared with animals with non-habitual behavior, animals with cocaine habitual behavior showed higher D1Rs and Ca v 1.2 expression in the Put accompanied with lower D2Rs and Ca v 1.3 expression in the Cd. However, after sucrose SA training, animals with habitual behavior only showed lower membrane expression of D2R in the Put than animals with non-habitual behavior. These results suggested that the upregulation of D1Rs-Ca v 1.2 signaling may lead to hyper-excitability of the Put, and the inactivation of D2Rs-Ca v 1.3 signaling may result in depressed activity in the Cd. This imbalance function between the Put and Cd, which causes an inability to shift between habits and goal-directed actions, may underlie the compulsive addiction habit.