Editors' ChoiceNeuroscience

When Breaking Up Is Not Depressing

Science Signaling  21 Dec 2010:
Vol. 3, Issue 153, pp. ec385
DOI: 10.1126/scisignal.3153ec385

The dopamine D1 and D2 receptors (D1R and D2R) can, like other G protein–coupled receptors, associate in heteromeric complexes. Noting that dysregulated dopamine signaling has been associated with mental illness, and that the D1R-D2R complex signals through a pathway distinct from those mediated by D1R or D2R in isolation, Pei et al. explored the possible role of the D1R-D2R complex in human pathophysiology. Postmortem analyses revealed increased coimmunoprecipitation of D1R and D2R from striatal tissues of individuals who had suffered major depression compared with that from control striata. After using affinity purification assays to identify regions of the two receptors crucial for formation of the complex, the authors constructed a cell-permeant peptide designed to disrupt this interaction (Tat-D2LIL3-29-2) and showed that it blocked agonist-dependent calcium release (indicative of signaling through the D1R-D2R complex) in human embryonic kidney (HEK) 293T cells coexpressing D1R and D2R. When infused bilaterally into rat prefrontal cortex, Tat-D2LIL3-29-2 decreased immobility in the forced swim test (an acute test of antidepressant-like activity) and also reduced coimmunoprecipitation of D1R by a D2R-specific antibody. Delivery of inescapable foot shock, an animal model for learned helplessness, led to increased coimmunoprecipitation of D1R from the rat prefrontal cortex and striatum by the D2R-specific antibody. Moreover, Tat-D2LIL3-29-2, like the antidepressant imipramine, decreased escape failure in rats that had developed learned helplessness in this paradigm. The authors thus conclude that the D1R-D2R complex may play some role in depression and that its disruption may provide a previously unexplored therapeutic strategy.

L. Pei, S. Li, M. Wang, M. Diwan, H. Anisman, P. J. Fletcher, J. N. Nobrega, F. Liu, Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects. Nat. Med. 16, 1393–1395 (2010). [PubMed]