Cordyceps sinensis (CS) is a fungus parasitic to Hepialidae larvae and has been known as a traditional medicine in China. Many studies have shown that CS possesses anti-fatigue, 1) antitumor, 2,3) antioxidant, 4,5) immunomodulatory, [6][7][8] hypoglycemic, 9,10) and vasorelaxant activities. 11) Since a relationship between depression and fatigue has been well established, [12][13][14] we determined to evaluate its antidepressive effect using the tail suspension test (TST) 15,16) that, in parallel with the forced swimming test, 17) has been proposed as a primary screening test for antidepressant drugs.The most prevalent theory for the pathogenesis of depression is the "monoamine hypothesis" in which monoamines (e.g., norepinephrine, dopamine, and serotonin) are thought to play important roles in the development of symptoms. Many antidepressant drugs work by modulating these neurotransmission systems. 18,19) Recently, behavioral tests have been used to study mechanisms underlying some antidepressant-like substances with inhibitors of neurotransmitters such as alpha-1 adrenoreceptor antagonists, selective dopamine D2 receptor antagonists, and serotonin synthesis inhibitors. [20][21][22][23] In addition to these screening behavioral tests of antidepressants, counting the numbers of head twitches induced by 5-hydroxytryptophan in mice is an effective method to evaluate serotoninerigic effects of drugs in vivo.24) It has been generally accepted that numbers of head twitches represent the level of 5-hydroxytryptamine (5-HT) in the synapses.In the present study, we have evaluated the antidepressantlike effects of hot water extract (HWCS) and supercritical fluid extract (SCCS), obtained from CS, using the TST in mice. We have also dissected the mechanism underlying the antidepressant actions of SCCS by examining the effects of pretreatment with an alpha-1 adrenoreceptor antagonist, a selective dopamine D2 receptor antagonist, and an inhibitor of serotonin synthesis. Furthermore, to determine whether the antidepressive effect of SCCS is mediated by the serotoninergic system, we have evaluated the effect of SCCS on 5-HTPinduced head twitch response in mice.
MATERIALS AND METHODSAnimals Five-week-old male C57 BL/6 mice were purchased from Japan SLC Inc. (Hamamatsu). They were housed in clear plastic cages (15ϫ22ϫ13 cm high) in groups of 5 mice per cage with free access to food and water. The temperature of the room in which the animals were housed, treated, and observed was maintained at 23Ϯ1°C with constant humidity (55Ϯ7%). The room was illuminated from 8:00 a.m. to 8:00 p.m. The animals were acclimatized for at least 5 d before behavioral experiments. All experiments were performed according to guidelines for the care and use of laboratory animals of the Keio University School of Medicine.Drug Treatment The following drugs were used: prazosin hydrochloride, (Ϯ)-sulpiride, DL-p-chlorophenylalanine (p-CPA), 5-hydroxy-L-tryptophan (5-HTP), fluoxetine hydrochloride, and polyoxyethylene sorbitan monooleate (Wako Pure Chemical...