Context: Hypericum caprifoliatum Cham & Schlecht (Guttiferae) extracts have a potential antidepressant-like effect in rodents. However, the molecular mechanisms by which these extracts exert this effect remain unclear.Objective: This study evaluated the effect of HC1, a fraction obtained from H. caprifoliatum enriched in phloroglucinol derivatives, on the Naþ ATPase activity in mouse brain and verified the influence of veratrine on the effect of HC1 in the forced swimming test (FST). Materials and methods: Veratrine (0.06 mg/kg) and HC1 (360 mg/kg) were given alone or combined i.p. 60 and p.o. 30 min, respectively, before FST. The effect of single and repeated administration (once a day for 3 consecutive days) of HC1 (360 mg/kg) on Na þ , K þ ATPase activity was evaluated ex vivo in the cerebral cortex and hippocampus of mice subjected or not to FST. Results: HC1 reduced the immobility time (103.15 AE 18.67 s), when compared to the control group (183.6 AE 9.51 s). This effect was prevented by veratrine (151.75 AE 22.19 s). Mice repeatedly treated with HC1 presented a significant increase in Na þ , K þ ATPase activity, both in cerebral cortex (46 AE 2.41 nmol Pi/minÁmg protein) and hippocampus (49.83 AE 2.31 nmol Pi/minÁmg protein), in relation to the respective controls (30 AE 2.66 and 29.83 AE 2.31 nmol Pi/minÁmg protein respectively). Discussion and conclusion: The HC1 antidepressant-like effect on FST might be related to its capacity to inhibit Na þ influx. HC1 increases hippocampal and cortical Na þ , K þ ATPase activities possibly through long-term regulatory mechanisms.