A physiological role for the dopamine D5 receptor as a regulator of BDNF and Akt signalling in rodent prefrontal cortex

The dopamine D-5 receptor (D5R) exhibits a wide distribution in prefrontal cortex (PFC) but its role in this region has not yet been elucidated. In the present study, we identified a novel physiological function for the D5R as a regulator of brain-derived neurotrophic factor (BDNF) and Akt signalling in PFC. Specifically, acute activation of the D5R by the dopamine agonist SKF 83959 enhanced BDNF expression and signalling through its receptor, tropomyosin receptor kinase B (TrkB), in rats and in mice gene-deleted for the D-1 receptor but not the D5R. These changes were concomitant with increased expression of GAD67, a protein whose down-regulation has been implicated in the aetiology of schizophrenia. Furthermore, D5R activation increased phosphorylation of Akt at the Ser(473) site, consequently decreasing the activity of its substrate GSK-3 beta. These findings could have wide-reaching implications given evidence showing activation of these pathways in PFC has therapeutic effects in neuropsychiatric disorders such as drug addiction, schizophrenia and depression.