1 D-04-00253 JPP 2005, 57: 1–6 ß 2005 The Authors Received September 23, 2004 Accepted February 2, 2005 DOI 10.1211/0022357056055 ISSN 0022-3573 Purimed R&D Institute, Kyunghee University, Hoeki- Dong, Dongdaemoon-Ku, Seoul 130-701, Korea Moonkyu Kang, Hyunsu Bae Department of Integrative Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea Kwang-Ho Pyun, Insop Shim Department of Pharmacology, College of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea Choon-Gon Jang Department of Psychology, Korea University, Seoul 136-701, Korea Hyuntaek Kim College of Oriental Medicine, Kyunghee University, Seoul 130-701, Korea Hyunsu Bae Correspondence: H. Bae, Purimed R&D Institute, Kyunghee University, Hoeki- Dong, Dongdaemoon-Ku, Seoul 130-701, Korea. E-mail: hbae@khu.ac.kr or I. Shim, Department of Integrative Medicine, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea. E-mail: ishim@khu. ac.kr Funding: This study was supported by a grant from the Korean Health 21 R&D Project, Ministry of Health & Welfare, Korea (02-PJI-PG11-VN01-SV04- 0054, 2002). Nelumbinis Semen reverses a decrease in hippocampal 5-HT release induced by chronic mild stress in rats Moonkyu Kang, Kwang-Ho Pyun, Choon-Gon Jang, Hyuntaek Kim, Hyunsu Bae and Insop Shim Abstract Depression is associated with a dysfunctional serotonin system. Recently, several lines of evidence have suggested that a very important evoking factor in depression may be a serotonin deficit in the hippocampus. This study assessed the antidepression effects of Nelumbinis Semen (NS) through increasing serotonin concentrations under normal conditions and reversing a decrease in serotonin concentrations in rat hippocampus with depression-like symptoms induced by chronic mild stress (CMS). Using an in-vivo microdialysis technique, the serotonin-enhancing effect of NS on rat hippo- campus was investigated and its effects compared with those of two well-known antidepressants, Hypericum perforatum (St John’s wort) and fluoxetine (Prozac). Rats were divided into five groups: saline-treated normal, without CMS; saline-pretreated control; NS-, St John’s wort- and fluoxetine- treated rats under CMS for 8 weeks or no stress treatment. NS and fluoxetine significantly increased serotonin in normal conditions and reversed a CMS-induced decrease in serotonin release in the hippocampus (P < 0.05 compared with normal group or control group under CMS). These results suggest that NS increases the serotonin levels normally decreased in depression, resulting in an enhancement of central serotonergic transmission and possible therapeutic action in depression. It is suggested that NS may present an antidepressant effect through enhancement of serotonin. Introduction Pathologies of the central nervous system (CNS) are generally associated with changes in the concentrations of neurotransmitters in specific brain regions (Crespi et al 2004). Assessment of neurotransmitter levels is important, therefore, in evaluating the effi- cacy of new pharmacological treatments. There is considerable clinical evidence that serotonin-containing pathways in the CNS play a significant role in the pathological development of major depression (van der Stelt et al 2004). Chronic stress is thought to impair the hippocampus, leading to a deficiency of serotonin in the hippocampus and the outbreak of depression (Penalva et al 2002; Dremencov et al 2003; Malberg & Duman 2003). In line with this notion, selective serotonin reuptake inhibitors (SSRIs) are a current mainstay for the treatment of major depression (van der Stelt et al 2004). The main action of antidepressants is to increase the amounts of such neurotransmit- ters in the synaptic space. SSRIs are highly effective and produce milder side effects than do tricyclic antidepressants (Khawaja et al 2004). Nelumbinis Semen has been widely used in Korean traditional medicine as a remedy for insomnia, anxiety and women’s depression following the menopause. We recently found this herbal medicine to have an antidepressant effect on rats under a forced swim-induced depression-like symptom (Kang 2005) as well as a chronic mild stress (CMS)-induced depression-like symptom (Jang et al 2004). There has been no direct indication, however, of an antidepressant effect through measurement of extracellular serotonin release by treatments with Nelumbinis Semen. This study assessed the direct increasing effect of Nelumbinis Semen on hippocampal serotonin release under normal and CMS conditions in rats using an in-vivo microdialysis technique coupled with HPLC. The results were then compared with the two well-known antidepressants Hypericum perforatum (St John’s wort) and fluoxetine (Prozac).