Modulation of D2R-NR2B Interactions in Response to Cocaine

Xian Yu Liu, Xiang Ping Chu, Li Min Mao, Min Wang, Hong Xiang Lan, Ming Hua Li, Guo Chi Zhang, Nikhil K K. Parelkar, Eugene E E. Fibuch, Michelle Haines, Kim A. Neve, Fang Liu, Zhi Gang Xiong, John Q. Wang

Research output: Contribution to journalArticlepeer-review

182 Scopus citations

Abstract

Dopamine-glutamate interactions in the neostriatum determine psychostimulant action, but the underlying molecular mechanisms remain elusive. Here we found that dopamine stimulation by cocaine enhances a heteroreceptor complex formation between dopamine D2 receptors (D2R) and NMDA receptor NR2B subunits in the neostriatum in vivo. The D2R-NR2B interaction is direct and occurs in the confined postsynaptic density microdomain of excitatory synapses. The enhanced D2R-NR2B interaction disrupts the association of Ca2+/calmodulin-dependent protein kinase II (CaMKII) with NR2B, reduces NR2B phosphorylation at a CaMKII-sensitive site (Ser1303), and inhibits NMDA receptor-mediated currents in medium-sized striatal neurons. Furthermore, the regulated D2R-NR2B interaction is critical for constructing behavioral responsiveness to cocaine. Our findings here uncover a direct and dynamic D2R-NR2B interaction in striatal neurons in vivo. This type of dopamine-glutamate integration at the receptor level may be responsible for synergistically inhibiting the D2R-mediated circuits in the basal ganglia and fulfilling the stimulative effect of psychostimulants.

Original languageEnglish (US)
Pages (from-to)897-909
Number of pages13
JournalNeuron
Volume52
Issue number5
DOIs
StatePublished - Dec 7 2006

Keywords

  • HUMDISEASE
  • MOLNEURO
  • SYSNEURO

ASJC Scopus subject areas

  • Neuroscience(all)

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