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Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects


We report that coupling between dopamine D1 and D2 receptors was markedly increased in postmortem brain of subjects suffering from major depression. Biochemical analyses revealed that D1 and D2 receptors form heterodimers via a direct protein-protein interaction. Administration of an interfering peptide that disrupts the D1-D2 receptor complex substantially reduced immobility in the forced swim test (FST) without affecting locomotor activity, and decreased escape failures in learned helplessness tests in rats.

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Figure 1: Characterization of D1R-D2R receptor complex formation.
Figure 2: Tat-D2IL3-29-2 treatment has antidepressant-like effects in vivo.


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We thank the Stanley Foundation Neuropathology Consortium for the brain samples. This work was supported by the Centre for Addictions and Mental Health (F.L.) and the Ontario Mental Health Foundation (J.N.N.). S.L. is a recipient of postdoctoral fellowship from the Heart and Stroke Foundation of Canada.

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Authors and Affiliations



L.P. and M.W. conducted the experiments associated with the protein-protein interactions. S.L. and M.D. performed the rat behavior experiments. H.A., P.J.F. and J.N.N. contributed to the behavior studies and manuscript editing. F.L. conceived and supervised the overall project and wrote the manuscript.

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Correspondence to Fang Liu.

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The authors declare no competing financial interests.

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Supplementary Figures 1–3, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 221 kb)

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Pei, L., Li, S., Wang, M. et al. Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects. Nat Med 16, 1393–1395 (2010).

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