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

Dysfunction of the dopamine neurotransmitter system has long been implicated in depression. Now, Fang Liu and colleagues show that the interaction between two dopamine receptor subtypes is increased in the brain of subjects with major depression. Blocking this interaction in rodent models of depression can result in 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.