Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Free, R.B. et al. J. Biol. Chem. 282, 21285–21300 (2007).
Lee, S.P. et al. J. Biol. Chem. 279, 35671–35678 (2004).
Rashid, A.J. et al. Proc. Natl. Acad. Sci. USA 104, 654–659 (2007).
Hasbi, A. et al. Proc. Natl. Acad. Sci. USA 106, 21377–21382 (2009).
Missale, C., Nash, S.R., Robinson, S.W., Jaber, M. & Caron, M.G. Physiol. Rev. 78, 189–225 (1998).
Fuxe, K. et al. Brain Res. Rev. 58, 415–452 (2008).
Lee, F.J., Pei, L. & Liu, F. Synapse 63, 710–712 (2009).
Agid, O., Kapur, S. & Remington, G. Expert Opin. Emerg. Drugs 13, 479–495 (2008).
Basso, A.M. et al. Neuropsychopharmacology 30, 1257–1268 (2005).
Cervo, L. & Samanin, R. J. Pharm. Pharmacol. 40, 155–156 (1988).
D'Aquila, P.S., Collu, M., Gessa, G.L. & Serra, G. Eur. J. Pharmacol. 405, 365–373 (2000).
Kapur, S. & Mann, J.J. Biol. Psychiatry 32, 1–17 (1992).
Muscat, R., Papp, M. & Willner, P. Biol. Psychiatry 31, 937–946 (1992).
Nutt, D.J. J. Clin. Psychiatry 67 Suppl 6, 3–8 (2006).
Yadid, G. & Friedman, A. Prog. Brain Res. 172, 265–286 (2008).
Yamada, J., Sugimoto, Y. & Yamada, S. Eur. J. Pharmacol. 504, 207–211 (2004).
Zisook, S., Rush, A.J., Haight, B.R., Clines, D.C. & Rockett, C.B. Biol. Psychiatry 59, 203–210 (2006).
Schwarze, S.R., Ho, A., Vocero-Akbani, A. & Dowdy, S.F. Science 285, 1569–1572 (1999).
Rush, A.J. et al. Am. J. Psychiatry 163, 1905–1917 (2006).
Pigott, H.E., Leventhal, A.M., Alter, G.S. & Boren, J.J. Psychother. Psychosom. 79, 267–279 (2010).
Acknowledgements
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–3, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 221 kb)
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1038/nm.2263
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.2263
This article is cited by
-
EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice
Molecular Psychiatry (2024)
-
Serum amyloid P component (SAP) modulates antidepressant effects through promoting membrane insertion of the serotonin transporter
Neuropsychopharmacology (2023)
-
D1R-5-HT2AR Uncoupling Reduces Depressive Behaviours via HDAC Signalling
Neurotherapeutics (2023)
-
PET imaging of animal models with depressive-like phenotypes
European Journal of Nuclear Medicine and Molecular Imaging (2023)
-
Development of a novel peptide to prevent entry of SARS-CoV-2 into lung and olfactory bulb cells of hACE2 expressing mice
Molecular Brain (2022)