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. 2014 Oct 10;30(6):1025–1035. doi: 10.1007/s12264-014-1473-9

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

Ying Zhang 1, Ning Wang 1, Ping Su 1, Jie Lu 1, Yun Wang 1,2,✉
PMCID: PMC5562559  PMID: 25304015

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

Footnotes

These authors contributed equally to this work

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