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Modulation of D2R-NR2B Interactions in Response to Cocaine (2006)

Modulation of D2R-NR2B Interactions in Response to Cocaine (2006)

  1. Jatelka
    Neuron 2006 Dec 7;52(5):897-909

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

    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 Ca(2+)/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.