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Dopamine Receptor Response to NMDA Stimulation

Dopamine D₁ receptors are evenly distributed in the plasma membrane of the direct pathway striatonigral neurons at rest, shown above by tagging D₁ receptors with a fluorescent marker and examining their expression in striatal neurons in culture (Figure). This technique shows D₁ receptor localization in cell body and plasma membrane of neurons but not in glia. Because D₁ receptors and the NMDA-sensitive glutamate receptor are known to interact functionally in the medium spiny neurons of the striatum, we studied the mechanism of this interaction. Stimulation of NMDA receptors with a direct acting agonist did, even in the presence of an NMDA-gated channel blocker, increase D₁ receptor-positive spines in the cells. In cell bodies, the proportion of D₁ receptors in the membrane relative to D₁ receptors in the cytosol (membrane/cytosol D₁ receptor ratio) significantly increased with NMDA receptor stimulation, but D₂ receptor localization was unaffected. At rest, a large fraction of the D₁ receptors freely diffuses within the plasma membrane. In the spines of dendrites, where both the NMDA and D₁ receptors can be associated with the postsynaptic density, the diffusion coefficient of the D₁ receptors is lower than in dendritic membrane. We were able to demonstrate that the reduced mobility of the D₁ receptors is the result of a direct interaction between D₁ and NMDA receptors that are allosterically transformed by occupation of the NMDA binding site. Specifically, the terminal end of D₁ receptors directly binds to the NR₁ subunit of the ligand-occupied NMDA receptor, effectively trapping D₁ receptors at the postsynaptic density when the NMDA receptors are stimulated. Notably, the binding of D₁ receptors to NR₁ is regulated by the occupation of the NMDA binding site but not by activation of the co-agonist site—the glycine receptor—nor by ion flow through the open NMDA ionophore. In summary, excitatory stimulation of the NMDA receptors will trap the D₁ receptors at the postsynaptic density, presumably making them stably available for dopaminergic stimulation and increasing the sensitivity of the postsynaptic density to dopamine itself. Conversely, this interaction could account for reduced D₁ receptor sensitivity in conditions characterized by reduced NMDA receptor activation. The allosteric modification of the ligand-occupied NMDA receptor, which can trigger the recruitment of D₁ receptors, but not D₂ receptors, to neuronal spines, represents a molecular mechanism for brain plasticity that could have an impact on cerebral development, function, and diverse psychiatric symptoms.

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Figure 1. The top two images show D1 receptor fluorescence tagging of a neuron in striatal culture (left) and extended focus projection from several confocal sections of a neuron (right). The bottom images show magnified segments of a dendritic tree, with stars indicating new D1 receptor-positive spines after NMDA treatment. Image adapted from Scott L, Zelenin S, Malmersjo S, Kowalewski JM, Markus EZ, Nairn AC, Greengard P, Brismar H, Aperia A: Allosteric changes of the NMDA receptor trap diffusible dopamine 1 receptors in spines. Proc Natl Acad Sci U S A 2006; 103:762–767.

Footnotes

Address reprint requests to Dr. Tamminga, UT Southwestern Medical Center, Department of Psychiatry, 5323 Harry Hines Blvd., #NE5.110, Dallas, TX 75390-9070; Carol.Tamminga{at}UTSouthwestern.edu (e-mail).

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