We have previously reported that Quercetin 3-O-b-D-apiofuranosyl-(1-->2)-[a-L-rhamnopyranosyl-(1-->6)]-b-D-glucopyranoside (CTN-986), a potential antidepressant extracted from glandless cottonseeds, exerted a notable antidepressant-like effect in experimental animal models. Recent evidence suggested, at least in some animal models, that the behavioral effects of chronic antidepressant treatment were mediated by the stimulation of hippocampal neurogenesis. To explore possible mechanisms of CTN-986's antidepressant-like effect, CTN-986 (10 mg/kg, i.g) or imipramine (IMI, 10 mg/kg, i.g) was administered once per day to the chronically stressed mice over 21 days. Immunohistochemical analysis revealed that chronic CTN-986 treatment increased bromodeoxyuridine (BrdU; thymidine analog as a marker for dividing cells)-positive cells in the hippocampal dentate gyrus in stressed mice, as was the case with chronic IMI treatment. Moreover, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and [3H] thymidine incorporation assay, it was found that exposure to CTN-986 for 4 days dose-dependently increased the proliferation of the cultured hippocampal neural progenitor cells (NPCs). This effect was significantly reversed by co-incubation with serotonin 1A (5-HT1A) receptor antagonist WAY100635. These results indicate that CTN-986 increase hippocampal NPCs proliferation which might be closely related to the activation of the 5-HT1A receptor. This finding can shed light on the mechanisms for its antidepressant-like effects.