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Fructus Akebiae (FAE) is a traditional Chinese herbal extract that has been used for the treatment of depressive disorders in China.Previous studies demonstrated that FAE displayed a potent antidepressant-like activity in forced swim and tail suspension tests.However,the underlying mechanism is unknown.Here we provide evidences that FAE enhanced the signaling of central monoamines via inhibition of the reuptake of the extracellular monoamines including serotonin (5-hydroxytryptamine, 5-HT) ,norepinephrine (NE) and dopamine (DA).In rat brain membrane preparation and HEK293 cells transfected with human serotonin transporter (SERT), NE transporter (NET) and DA transporter (DAT), we found that that FAE displayed marked affinity to rat and cloned human monoamine transporters in ex vivo and in vitro experiments, using competitive radio ligand binding assay.In uptake assays using rat synaptosomes and transfected cells, FAE was found to significantly inhibit all three monoamine transporters in a dose-and time-dependent manner, with a comparable or better potency to their corresponding specific inhibitors.In contrast, FAE 10 μmol · L-1 , showed no significant affinity to a variety array of receptors tested from CNS.In support of our uptake data, in vivo microdialysis study showed that administration of FAE 12.6, 25 and 50 mg· kg-1 significantly increased extracellular concentrations of 5-HT, NE and DA in frontal cortex of freely moving rats.Take together, our current study showed for the first time that FAE is a novel triple inhibitor of monoamine transporters, which may be one the mechanisms of its antidepressant activity.