1Neuroscience 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, Beijing 100191, China
2PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China
#These authors contributed equally to this work.

Abstract 

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 D1R 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-D1R 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 D1R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders.

Keywords

protein kinase D1; dopamine D1 receptor; phosphorylation; cocaine; addiction; conditioned place preference; locomotor activity

[SpringerLink]