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Depression is associated with behavioral disturbances and serotonergic and neuroendocrinological disfunctions.1,2) The brain serotonergic system is a very complicated control system playing an important role in the response to depression. 3)A number of factors have been proposed to account for a reduced functionality of serotonergic system in depression. Investigations based on this system have formed into currently available antidepressants.2) On the other hand, neuroendocrinological abnormality in depressed patients is hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis characterized by hypersecretion of corticotropin-releasing factor (CRF), which stimulates corticosterone release. 4,5) Successful antidepressant treatment could attenuate these alterations in clinical trials and animal experiments. [6][7][8][9] In addition, there is a close relationship between the serotonergic and HPA axis systems in major depression. [10][11][12][13] The impact of stress on the HPA axis is reviewed and evidence present that CRF is the stress neurotransmitter which plays an important role in the activation of serotonergic systems. 11,14) Psoralen (Fig. 1) is a main furocoumarin isolated from the seeds of Psoralea corylifolia, 15) which is a traditional Chinese medicine used to treat a wide range of diseases and conditions. Our previous studies demonstrated that the total furocoumarins extracts of P. corylifolia possessed the potent antidepressant properties by employing the forced swimming test (FST), a well-established animal model of depression. 7)These furocoumarins extracts depressed the hyperactive HPA axis induced by swim stress in mice.7) Furthermore, the total furocoumarins extracts and psoralen exhibited inhibitory actions on monoamine oxidase (MAO) A and B activities. 16,17) Per-orally administered psoralen increased the daytime levels of melatonin via the competitive inhibition of hepatic melatonin metabolism, indicating that psoralen might affect seasonal affective disorder patients under a low level of illumination.18) However, there is no study on antidepressant-like effects and related possible mechanisms of actions by psoralen. The aim of the current study was to investigate the effects of psoralen on the durations of immobility, climbing and swimming in the mouse FST after administrations for 1, 3, 7 and 14 d, respectively. We also examined the effects of 14-d psoralen treatment on serotonergic neurotransmitters serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels in frontal cortex and hippocampus of the mouse brain regions. The regulation of psoralen on the HPA axis including CRF and corticosterone concentrations was simultaneously studied in the mouse FST. MATERIALS AND METHODS MaterialsPsoralen was isolated and purified from the seeds of P. corylifolia as described in our previous reports. 19)The purity of the chemical was determined to beyond 98% by HPLC analysis. Amitriptyline was obtained from Changzhou Siyao Pharmaceuticals Co., Ltd. (P. R. China). All other chemical...