Disruption of dopamine D1 receptor phosphorylation at serine 421 attenuates cocaine-induced behaviors in mice  

作　　者：Ying Zhang Ning Wang Ping Su Jie Lu Yun Wang 

机构地区：[1]Neuroscience Research Institute and Department of Neurobiology,The Key Laboratory for Neuroscience of the Ministry of Education/National Health and Family Planning Commission,Peking University Health Science Center [2]PKU-IDG/Mc Govern Institute for Brain Research,Peking University

出　　处：《Neuroscience Bulletin》2014年第6期1025-1035,共11页神经科学通报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (91332119,81161120497,30925015,30830044,31371143,30900582 and 81221002);the National Basic Research Development Program from the Ministry of Science and Technology of China (2014CB542204)

摘　　要：Dopamine D1 receptors（D1Rs） play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1 R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1 R in the forebrain. These transgenic mice showed reduced phospho-D1R（S421） and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1 R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1 R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders.Dopamine D1 receptors（D1Rs） play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1 R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1 R in the forebrain. These transgenic mice showed reduced phospho-D1R（S421） and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1 R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1 R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders.

关 键 词：protein kinase D1 dopamine D1 receptor PHOSPHORYLATION COCAINE ADDICTION conditioned place preference locomotor activity 

分 类 号：R749.64[医药卫生—神经病学与精神病学]