Noradrenaline activation of hippocampal dopamine D₁ receptors promotes antidepressant effects

Dopamine D₁ receptors (D₁Rs) in the hippocampal dentate gyrus (DG) are essential for antidepressant effects. However, the midbrain dopaminergic neurons, the major source of dopamine in the brain, only sparsely project to DG, suggesting possible activation of DG D₁Rs by endogenous substances other than dopamine. We have examined this possibility using electrophysiological and biochemical techniques and found robust activation of D₁Rs in mouse DG neurons by noradrenaline. Noradrenaline at the micromolar range potentiated synaptic transmission at the DG output and increased the phosphorylation of protein kinase A substrates in DG via activation of D₁Rs and β adrenergic receptors. Neuronal excitation preferentially enhanced noradrenaline-induced synaptic potentiation mediated by D₁Rs with minor effects on β-receptor-dependent potentiation. Increased voluntary exercise by wheel running also enhanced noradrenaline-induced, D₁R-mediated synaptic potentiation, suggesting a distinct functional role of the noradrenaline-D₁R signaling. We then examined the role of this signaling in antidepressant effects using mice exposed to chronic restraint stress. In the stressed mice, an antidepressant acting on the noradrenergic system induced a mature-to-immature change in the DG neuron phenotype, a previously proposed cellular substrate for antidepressant action. This effect was evident only in mice subjected to wheel running and blocked by a D₁R antagonist. These results suggest a critical role of noradrenaline-induced activation of D₁Rs in antidepressant effects in DG. Experience-dependent regulation of noradrenaline-D₁R signaling may determine responsiveness to antidepressant drugs in depressive disorders.