抄録
Background
Major depression is a psychiatric disorder with high lifetime prevalence. Selective serotonin reuptake inhibitors (SSRIs) are commonly used for treatment of depression, but mechanisms of SSRIs to improve symptoms of depression are not fully understood. In addition, development of improved treatments especially for treatment-resistant depression is desired. Recently, chronic administration of SSRI is reported to increase the expression of dopamine D1 receptors in mature granule cells of the hippocampal dentate gyrus. In this study, we investigated the role of D1 receptors in the dentate gyrus in antidepressant actions of SSRIs.
Methods
Mice were treated with fluoxetine, an SSRI, chronically by subcutaneous implantation of matrix-driven delivery pellets (15 mg/kg/day, 14 days). The fluoxetine-induced changes in gene and protein expression were analyzed by quantitative real-time PCR and Western blot analysis, respectively. In addition, depression-like behaviors were evaluated with the novelty-suppressed feeding test (NSFT) and tail suspension test (TST) in mice subjected to chronic restraint stress.
Results
Chronic treatment with fluoxetine induced the expression of D1 receptor mRNA and protein in the dentate gyrus, but not other subtypes of dopamine receptor mRNA. Regular restraint stress (2 hr/day, 14 days) increased the feeding latency in the NSFT, and chronic treatment with fluoxetine reduced the increased feeding latency. However, in mice subjected to severe restraint stress (4 hr/day, 28 days), chronic treatment with fluoxetine failed to reduce the stress-induced increase in feeding latency in the NSFT and immobility time in the TST. Chronic co-administration of a dopamine D1 receptor agonist, R(+)-SKF81297 (1.5 mg/kg/day, i.p. for 5 days), with fluoxetine resulted in the reversal of the depression-like behaviors.
Conclusions
These results suggest that activation of dopamine D1 receptors in the dentate gyrus enhances therapeutic actions of SSRI. D1 receptors may be a therapeutic target in combination with SSRI antidepressants under SSRI-resistant stress conditions.
