[Introduction]
Several clinical studies have reported that augmentation therapy consisting of a combination of antidepressants with 5-HT1A receptor agonist treatment is a better therapeutic strategy for major depressive disorder than antidepressant monotherapy. However, the mechanism underlying the clinical efficacy of augmentation therapy is poorly understood. Accumulating evidences suggested that hippocampal neurogenesis may contribute to exert therapeutic effect of antidepressants. Then, we designed this study in order to elucidate the effect of augmentation therapy on neurogenesis in rat hippocampus under psychosocial stress condition.
[Methods]
Sprague-Dawley rats were used in all experiment. Animals were administered intraperitoneally with saline, fluoxetine (FLX, 5mg/kg), tandospirone (TDS, 10mg/kg) or FLX plus TDS once daily for 28 days. Using resident-intruder paradigm, intruder rats were experienced four social defeat exposures within the last half 2 weeks of drug treatment. Defeated intruders were transcardially perfused with 4% paraformaldehyde. Brains were cut into 40μm coronal section using a freezing microtome. For stereological quantification of newly generated neurons in the dentate gyrus (DG) of hippocampus, the estimate of doublecortin (DCX)-immunoreactive cell numbers were determined using the optical fractionator procedure.
[Results]
Chronic treatment with FLX or TDS reversed the stress-induced decrease in the number of DCX-positive cells in the DG of hippocampus. Concomitant administration of FLX and TDS showed an about twice increase in the number of DCX-positive cells compared to the other groups.
[Discussion]
In the present study, augmentation therapy consisting of a combination of FLX with TDS drastically increased the number of DCX-immunoreactive cells in the DG of hippocampus compared to monotherapy of FLX or TDS. These results suggest that the clinical efficacy of augmentation therapy might be partly mediated by increasing hippocampal neurogenesis.