Abstract
Depression is a leading cause of disability. Current pharmacological treatment of depression is insufficient, and development of improved treatments especially for treatment-resistant depression is desired. Understanding the neurobiology of antidepressant actions may lead to development of improved therapeutic approaches. Here, we demonstrate that dopamine D1 receptors in the dentate gyrus act as a pivotal mediator of antidepressant actions in mice. Chronic administration of a selective serotonin reuptake inhibitor (SSRI), fluoxetine, increases D1 receptor expression in mature granule cells in the dentate gyrus. The increased D1 receptor signaling, in turn, contributes to the actions of chronic fluoxetine treatment, such as suppression of acute stress-evoked serotonin release, stimulation of adult neurogenesis and behavioral improvement. Importantly, under severely stressed conditions, chronic administration of a D1 receptor agonist in conjunction with fluoxetine restores the efficacy of fluoxetine actions on D1 receptor expression and behavioral responses. Thus, our results suggest that stimulation of D1 receptors in the dentate gyrus is a potential adjunctive approach to improve therapeutic efficacy of SSRI antidepressants.
Highlights
Depression is one of the most common psychiatric disorders, but the etiology of depression is not fully understood [1,2,3]
Analyses along the dorsoventral axis revealed that chronic fluoxetine treatment increased Drd1 mRNA both in the dorsal and ventral parts of the dentate gyrus, the expression level of Drd1 mRNA was lower in the ventral part than in the dorsal part (Supplementary Figure 1g)
This study demonstrated that chronic treatment with the antidepressant, fluoxetine, induced transcriptional activation of the Drd1 gene in mature granule cells of the dentate gyrus
Summary
Depression is one of the most common psychiatric disorders, but the etiology of depression is not fully understood [1,2,3]. In animal models of depression, chronic stress and antidepressant treatment induce molecular and cellular changes in hippocampal neurons [2, 5]. Previous studies showed that chronic administration of fluoxetine (an SSRI) induces the increased expression of dopamine D1 receptors and the immature properties in dentate granule cells, which are called dematuration [12, 13]. We further investigated roles of D1 receptors selectively induced in the dentate gyrus by antidepressants. Biochemical and behavioral analyses revealed that the increase in D1 receptor signaling in mature granule cells in the dentate gyrus was essential for the antidepressant actions. Our results raise the possibility that the D1 receptor in granule cells may be a therapeutic target to enhance antidepressant actions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
