Shinohara Fumiya, Kamii Hironori, Minami Masabumi, Kaneda Katsuyuki
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University.
Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University.
Biol Pharm Bull. 2017;40(11):1983-1989. doi: 10.1248/bpb.b17-00614.
The expression phase of cocaine-induced conditioned place preference (CPP) represents a cocaine-seeking behavior triggered by contextual cues associated with the rewarding effects of cocaine. However, the exact mechanisms underlying the cocaine CPP expression remain unclear. Here, we investigated the role of dopaminergic (DAergic) transmission in the medial prefrontal cortex (mPFC) for the expression of cocaine CPP. An intra-ventral tegmental area (VTA) injection of a cocktail of γ-aminobutyric acid (GABA) and GABA receptor agonists (baclofen and muscimol, respectively) immediately before the posttest inhibited the expression of cocaine CPP. An intra-mPFC injection of a dopamine D1 but not D2 receptor antagonist before the posttest significantly attenuated CPP expression. Moreover, after the posttest, the number of cFos-positive mPFC neurons in rats that were conditioned with cocaine was significantly larger than that with saline. Additionally, photostimulation of channelrhodopsin-2 expressing fibers derived from the VTA induced cFos expression in the mPFC, and this induction was reduced by a prior systemic injection of a D1 receptor antagonist. These findings indicate that during the expression of cocaine CPP, enhanced DAergic transmission from the VTA to the mPFC stimulates D1 receptors; this results in the activation of mPFC neurons, further leading to the expression of cocaine CPP.
可卡因诱导的条件性位置偏爱（CPP）的表达阶段代表了一种由与可卡因奖赏效应相关的情境线索触发的觅药行为。然而，可卡因CPP表达背后的确切机制仍不清楚。在此，我们研究了内侧前额叶皮质（mPFC）中多巴胺能（DAergic）传递在可卡因CPP表达中的作用。在测试后立即向腹侧被盖区（VTA）注射γ-氨基丁酸（GABA）和GABA受体激动剂（分别为巴氯芬和蝇蕈醇）的混合物可抑制可卡因CPP的表达。在测试后向mPFC注射多巴胺D1受体拮抗剂而非D2受体拮抗剂可显著减弱CPP表达。此外，在测试后，用可卡因进行条件化的大鼠中cFos阳性mPFC神经元的数量显著多于用生理盐水进行条件化的大鼠。另外，对源自VTA的表达通道视紫红质-2的纤维进行光刺激可诱导mPFC中的cFos表达，而预先全身注射D1受体拮抗剂可减少这种诱导。这些发现表明，在可卡因CPP表达期间，从VTA到mPFC的增强的多巴胺能传递刺激D1受体；这导致mPFC神经元的激活，进而导致可卡因CPP的表达。
