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Ginsenoside Rb 3 has been proved to have antidepressant-like effects, which possesses 1 xylose and 3 glucose moieties with 20( S )-protopanaxadiol (PPD) as the aglycone. However, it is commonly accepted that orally ingested ginsenosides can be deglycosylated or partially deglycosylated into active derivatives by the intestinal bacteria. To identify potential antidepressant drug candidates, we compared the antidepressant-like activities between ginsenoside Rb 3 and its four deglycosylated derivatives, Rg 3 , Rh 2 , compound K (C-K), and PPD. Effects of acute (1-day), short chronic (7-days), and longer chronic treatments (14-days) with these ginsenosides (50 and 100 mg/kg, p.o.) on the behavioral changes in the forced swim test (FST), tail suspension test (TST) and open field test were investigated. Serum corticosterone and adrenocorticotropic hormone (ACTH) levels and mouse brain monoamine neurotransmitters 5-HT, NA and DA levels were measured using commercially available competitive enzyme-linked immunosorbent assay (ELISA) kits. Interestingly, C-K showed antidepressant-like activities similar to that of Rb 3 , and Rg 3 displayed antidepressant-like effects at lower dosage and faster time, indicating it has better effects than Rb 3 , whereas Rh 2 and PPD failed to show any effect. Our results also showed, unlike the positive control fluoxetine, Rb 3 , Rg 3 and C-K significantly increased the NA levels in the brain regions of mice exposed to FST but did not affect the 5-HT and DA levels. Moreover, treatment with Rg 3 could reverse swim stress-induced increased levels of serum ACTH and corticosterone. These results suggest that C-K and Rg 3 are the active deglycosylated derivatives, especially the latter compound, which is more potent than Rb 3 and exerts antidepressant-like effects by regulating NA, ACTH and corticosterone levels. [ABSTRACT FROM AUTHOR]