Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi-ken, Sendai-shi, Aoba-Ku, Aramaki, Aoba 6-3, Sendai, 980-8578, Japan.
Department of Pharmacology and Clinical Pharmacy Faculty of Pharmacy, Universitas Padjadjaran, JL. Raya Bandung-Sumedang KM 20.5 Jatinangor, Sumedang, Jawa Barat, 45363, Indonesia.
Mol Neurobiol. 2019 Dec;56(12):7911-7928. doi: 10.1007/s12035-019-1635-x. Epub 2019 May 25.
Nicotine in tobacco causes psychological dependence through its rewarding effect in the central nervous system (CNS). Although nicotine dependence is explained by dopamine receptor (DR) signaling together with nicotinic acetylcholine receptors (nAChRs), the synaptic molecular mechanism underlying the interaction between dopamine receptor and nAChRs remains unclear. Since reward signaling is mediated by dopamine receptors, we hypothesized that the dopamine D2 receptor (D2R), in part, mediates the synaptic modulation of nicotine-induced conditioned place preference (CPP) in addition to dopamine D1 receptor. To investigate the involvement of D2R, wild-type (WT) and dopamine D2 receptor knockout (D2RKO) mice were assessed using the CPP task after induction of nicotine-induced CPP. As expected, D2RKO mice failed to induce CPP behaviors after repeated nicotine administration (0.5 mg/kg). When kinase signaling was assessed in the nucleus accumbens and hippocampal CA1 region after repeated nicotine administration, both Ca/calmodulin-dependent protein kinase (CaMKII) and extracellular signal-regulated kinase (ERK) were upregulated in WT mice but not in D2RKO mice. Likewise, nicotine-induced CPP was associated with elevation of pro- brain-derived neurotropic factor (BDNF) and BDNF protein levels in WT mice, but not in D2RKO mice. Taken together, in addition to dopamine D1 receptor signaling, dopamine D2 receptor signaling is critical for induction of nicotine-induced CPP in mice.
烟草中的尼古丁通过其在中枢神经系统（CNS）中的奖赏作用引起心理依赖。尽管尼古丁依赖通过多巴胺受体（DR）信号与烟碱型乙酰胆碱受体（nAChRs）共同解释，但多巴胺受体和 nAChRs 之间相互作用的突触分子机制仍不清楚。由于奖赏信号是由多巴胺受体介导的，我们假设多巴胺 D2 受体（D2R）部分介导了尼古丁诱导的条件位置偏爱（CPP）的突触调制，除了多巴胺 D1 受体之外。为了研究 D2R 的参与，使用 CPP 任务评估了野生型（WT）和多巴胺 D2 受体敲除（D2RKO）小鼠在诱导尼古丁诱导的 CPP 后。正如预期的那样，在重复给予尼古丁（0.5 mg/kg）后，D2RKO 小鼠未能诱导 CPP 行为。当在重复给予尼古丁后评估伏隔核和海马 CA1 区的激酶信号时，Ca/calmodulin 依赖性蛋白激酶（CaMKII）和细胞外信号调节激酶（ERK）在 WT 小鼠中上调，但在 D2RKO 小鼠中没有上调。同样，在 WT 小鼠中，尼古丁诱导的 CPP 与脑源性神经营养因子（BDNF）前体的升高有关和 BDNF 蛋白水平，但在 D2RKO 小鼠中没有。总之，除了多巴胺 D1 受体信号外，多巴胺 D2 受体信号对于诱导小鼠中的尼古丁诱导的 CPP 至关重要。
