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JPP 2005, 57: 1–6ß 2005 The AuthorsReceived September 23, 2004Accepted February 2, 2005 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, 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 Purimed R&D Institute,Kyunghee University, Hoeki- 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 The Catholic University of Korea,Seoul 137-701, Korea 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.
College of Pharmacy,Sungkyunkwan University,Suwon 440-746, Korea Department of Psychology,Korea University, Seoul 136-701, 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).
Seoul 130-701, Korea. or I. Shim, 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 Ministry of Health & Welfare,Korea (02-PJI-PG11-VN01-SV04- HPLC. The results were then compared with the two well-known antidepressants Hypericum perforatum (St John’s wort) and fluoxetine (Prozac).
collector. Three baseline samples were collected beforetreatments. Dialysate samples were collected every20 min for 2 h following all injections. Samples (injection volume, 20 L) were assayed for serotonin using an HPLC system equipped with an electrochemical detector (ESA Korea), weighing 220–250 g at the start of the experiment, Coulochem II- 5200B). Separation of serotonin was per- were used. Rats were kept on a 12-h light–dark cycle in formed on an LC-8-DB 3-m column (150 Â 4.6 mm; individual home cages with food and water freely available.
Supecol, Bellefonte, PA). The mobile phase (0.05 M mono- All experiments were approved by the KHU Institutional basic sodium phosphate, 0.1 N sodium acetic acetate, 1% Animal Care and Use Committee abided by International methanol, pH 4.4 with H3PO4) was pumped at a flow rate Animal Care and Use Committee regulation.
of 1.0 mL minÀ1. Serotonin content in the variousdialysates was expressed as a percentage of baselinerelease measured as the mean of the final 3 samples.
Rats were randomly divided into two groups, one exposedto a variety of chronic mild stressors (CMS group) and the other an unstressed normal group (control group). CMS After 2 h of baseline data had been collected, rats received procedures, similar to those we have previously reported, either 100, 400 or 1000 mg kgÀ1 of NS, 500 mg kgÀ1 of St were employed for this study (Kim et al 2003). Briefly, John’s wort, 10 mg kgÀ1 of fluoxetine, or the saline vehicle CMS rats were subjected for eight weeks to a weekly under normal or stress conditions. Each drug was dis- regimen of stressors, including two periods of water and solved in isotonic sodium chloride (0.9%) and adminis- food deprivation (20 h), one period of either water (14 h) tered orally (Nelumbinis Semen and St John’s wort) or or food deprivation (2 h), two periods (7 h and 17 h) of 45 intraperitoneally (fluoxetine) to rats for 1 day before cage tilt, one period in a soiled cage (100 mL of water in assessment of serotonin or for 8 weeks CMS before sawdust bedding per individual cage), two periods (3 h and 5 h) of white noise (85 dB), three periods (9 h) ofstroboscope light (300 flashes/min) and one period (17 h)of group housing (5 rats per cage). Normal rats were housed in a separate room and received a daily oraladministration of 0.9% saline, but did not receive any At the end of the experiment, rats were perfused transcar- stress, (Normal group (C), n ¼ 10). Stressed groups dially, under deep pentobarbital anaesthesia, with normal received a daily oral administration of 0.9% saline saline followed by a 10% formalin solution. The brains (Stress control group (S), n ¼ 8), NS 100 mg kgÀ1 (n ¼ 6), were removed from the skulls and stored in 10% formalin NS 400 mg kgÀ1 (n ¼ 7), NS 1000 mg kgÀ1 (n ¼ 6) or St for at least 2 weeks, after which 50-m cryostat sections John’s wort (500 mg kgÀ1, n ¼ 7) or intraperitoneal fluox- were cut through the sites of the microdialysis probes and etine (10 mg kgÀ1, n ¼ 6) during the stress treatment.
subsequently stained with cresyl violet to identify the loca-tion of the probe.
Surgery, microdialysis and analytical procedure At least one week before the start of the experiment,rats were anaesthetized with sodium pentobarbital Data were statistically analysed by one-way analysis of (50 mg kgÀ1, i.p.) and, using aseptic techniques, guide variance. Differences among the groups were further ana- cannulae (CMA/Microdialysis, Solna, Sweden) aimed to terminate in the hippocampus (AP ¼ 1.8, DV ¼ 5.7,L ¼ 4.8 from bregma) were stereotaxically implanted andattached to the skull using skull screws and dental cement as previously described by Paxinos & Watson (1986).
After the last day of the CMS schedule, all rats were left Effect of Nelumbinis Semen on extracellular without any treatment for at least 24 h. On the following serotonin release in the hippocampus under day, a 3-mm vertical dialysis probe (CMA12, CMA/ Microdialysis) connected via a dual liquid swivel to asyringe Figures 1A and 1B compare the effect, on rat hippocam- inserted into the guide cannula and perfused at a pal serotonin concentration, of normal, NS, St John’s constant rate of 1.0 L minÀ1 with artificial cerebrospinal wort and fluoxetine without CMS. The mean values of fluid (ACSF; composition in mM: 145 NaCl, 2.7 KCl, dialysate serotonin in the hippocampus at 20 min after 1.2 CaCl2, 1.0 MgCl2 and 2.0 Na2HPO4, pH 7.4). Rats drug injections were 19.5 Æ 2.9, 20.1 Æ 2.2, 23.3 Æ 1.8, were then placed in the cage and the outlet tubing 23.6 Æ 1.9, 21.8 Æ 1.9 and 28.3 Æ 4.1 pg/20 L for the nor- connected to a microfraction collector (CMA142, CMA/ mal control (C), NS 100, NS 400, NS 1000, St John’s Microdialysis). The dialysate was collected during 20-min wort (JWE) and fluoxetine (F)-treated groups, respec- sampling intervals in plastic microvials on the fraction tively. Oral administration of 400 and 1000 mg kgÀ1 of Nelumbinis Semen reverses stress-induced decrease in rat hippocampal 5-HT release Effect of Nelumbinis Semen on extracellular serotonin Effects of Nelumbinis Semen on extracellular serotonin con- concentrations in the hippocampus at the peak, 20 min (A), and centrations in the hippocampus at the peak, 20 min (A), and time course time course of its changes (B), after drug injections, as measured by of its changes (B), after drug injections, as measured by microdialysis in microdialysis in rats under normal conditions. Each bar represents rats under chronic mild stress (CMS) conditions. Each bar represents the the mean value Æ s.e.m. from ten rats per group for the six treatment mean value Æ s.e.m. from 6–10 rats per group for the seven treatment groups: saline-treated normal group without any drug treatment (C), groups: saline-treated normal group without any treatment (C), saline- Nelumbinis Semen treatment group (NS1 (100 mg kgÀ1 p.o.), NS2 treated stress group under CMS (S), Nelumbinis Semen treatment group (400 mg kgÀ1 p.o.), NS3 (1000 mg kgÀ1 p.o.)), St John’s wort treat- under CMS (NS1 (100 mg kgÀ1 p.o.), NS2 (400 mg kgÀ1 p.o.), NS3 ment group (JWE) and fluoxetine treatment group (F). *P < 0.05, (1000 mg kgÀ1 p.o.)), St John’s wort treatment group under CMS **P < 0.01, compared with normal control group (C) based on one- (JWE), and fluoxetine treatment group under CMS (F). *P < 0.05 way analysis of variance followed by post-hoc LSD test.
compared with C group; or #P < 0.05 compared with S group basedon one-way analysis of variance followed by post-hoc LSD test.
NS significantly increased the concentration of normal seen in Figures 1A and 1B. These results suggest that NS serotonin (P < 0.05 for normal controls (100 Æ 15%, has a significant antidepressant effect by causing an n ¼ 10) vs NS 400 (119 Æ 5.9%, 19% increase compared increase in serotonin concentration even in the normal with normal controls, n ¼ 10) and for normal control vs NS 1000 (121 Æ 8.2%, 21% increase compared with nor-mal controls, n ¼ 10)). A similarly significant increase was Effect of Nelumbinis Semen on extracellular seen in the fluoxetine-treated group, although St John’s serotonin release in the hippocampus under CMS wort treatment did not significantly increase the concen-tration of normal serotonin (P < 0.05 for normal controls Figures 2A and 2B compare the effect, on changes of (100 Æ 15%, n ¼ 10) vs fluoxetine (145 Æ 14.6%, 45% increase compared with normal controls, n ¼ 10) and for hippocampus, of saline-pretreated normal without CMS normal controls vs St John’s wort (112 Æ 8.5%, 12% (C) and stress control without drug treatment (S), NS, increase compared with normal controls, n ¼ 10)), as St John’s wort (JWE) and fluoxetine (F) under CMS for 8 weeks. As seen in Figure 2A, the mean values of dialy- In a recent study, we found that Nelumbinis Semen sate 5-HT in the hippocampus at 20 min after drug injec- (NS) had a distinct antidepressant effect in that it reduced tions were 20.0 Æ 3.4, 13.7 Æ 1.9, 14.3 Æ 1.6, 14.9 Æ 2.0, the immobility time of rats in the forced swim (Kang et al 16.3 Æ 1.4, 14.7 Æ 2.1 and 16.7 Æ 2.6 pg/20 l for the nor- 2005), reversing decreases of sucrose intake and serotonin mal, stress control, NS 100, NS 400, NS 1000, St John’s (5-HT)1A receptor binding in hippocampus (5-HT1A wort, and fluoxetine-treated groups, respectively. The hetero-receptors) induced by CMS (Jang et al 2004). It is basal serotonin levels in the stress group were lower than known that NS contains various alkaloids (Table 1) in the saline-pretreated normal group, and this effect was (Zelenski 1977; Wang et al 1991). Of these components, statistically significant in either group (P < 0.05 for sal- anonaine, asimilobine, isoquercitrin, hyperoside, lirinidine ine-pretreated control (68.5 Æ 14.2%, n ¼ 8) vs normal and nornuciferine have been most widely recognized as control (100.0 Æ 17.0%, n ¼ 10)) as shown in Figure 2A.
having antidepressant effects, as evaluated by neurotrans- Oral administration of 1000 mg kgÀ1 NS significantly mitter reuptake inhibition and the forced swimming test reversed the decrease in serotonin concentration induced (Shoji et al 1987; Protais et al 1995; Hasrat et al 1997; (68.5 Æ 14.2%, n ¼ 8) vs NS 1000 (81.4 Æ 8.9%, n ¼ 6)).
It has been established that depressed patients have a A similar reversal by NS is presented in the fluoxetine dysfunctional serotonin system (Leitch et al 2003). Such a treatment but not in the St John’s wort treatment dysfunction is thought to cause loss in postsynaptic sig- (P < 0.05 for saline-pretreated control (68.5 Æ 14.2%, nalling mechanisms and a stress-induced impairment in n ¼ 8) vs fluoxetine (83.5 Æ 15.5%, 15.5% increase com- the hypothalamic-pituitary-adrenal (HPA) axis, a major pared with saline-pretreated control, n ¼ 6); P > 0.05 for receptive site of stress. This results in impairment of the saline-pretreated control (68.5 Æ 14.2%, n ¼ 8) vs St hippocampus and its very well developed serotonergic John’s wort (73.5 Æ 14.1%, 5% increase compared with nerve system, the most sensitive area for impairment of saline-pretreated control, n ¼ 7)) at the peak, relative to the HPA axis (Dremencov et al 2003). The hippocampus baseline, as seen in Figures 2A and 2B. These results also controls many of the brain functions that, when suggest that NS has a significant antidepressant effect by altered, disturb patients. These include regulation of neu- increasing serotonin concentration under CMS, similar to roendocrine and autonomic functions, mood and cogni- tion difficulties, adverse responses to stressful stimuli, andothers. Hippocampal functions are highly regulated byserotonergic systems (Hjorth et al 2000). The hippocam- pus is thus suggested to play a critical role in depressivedisorders. It should be noted that fluoxetine, as a potent Major depression is a severe disorder that involves distur- SSRI, significantly increased the concentrations of normal bances of autonomic, cognitive, endocrine and emotional serotonin, but St John’s wort treatment did not. These functions. Depressive disorders affect a large population results suggest that fluoxetine increases serotonin release (an estimated 9–10% of adults) in the United States and, in turn, produces an antidepressant effect, whereas (Regier et al 1993). Because of its severity, a quick and St John’s wort may produce antidepressant effects effective treatment of the illness is often required.
Exposure to chronic stress is thought to precipitate orexacerbate depression, and several studies suggest thatrepeated, weak stressors are effective methods of inducing depression-like symptoms in an animal model. Such animal models reflect symptoms of depression in man commonly attributed to weak, consistent and chronic stress in modern society. The model of chronic mild stress (CMS) developed by Willner and colleagues is one of the most widely accepted animal models of depression, characterized by a high degree of validity and reliability (Katz 1981; Willner 1991).
In a typical experiment involving the Willner model, rats (Willner et al 1987) or mice (Monleon et al 1995) are consistently exposed to various mild stressors, such as overnight illumination, food or water deprivation, cage tilt and change of cage mate. This procedure induces anhedonia. Furthermore, it decreases consumption and preference for palatable weak (1–2%) sucrose solution, which is concrete behaviour of anhedonia present in the animals under CMS. Treatment with most antidepressants causes the consumption of sucrose solution to return to normal (Muscat et al 1992). The CMS model was chosenfor this study because the ease with which a depression- This table was referred from Nelumbinis Semen reverses stress-induced decrease in rat hippocampal 5-HT release through other neurotransmitter systems such as dopamine of central nervous system (CNS) neuromediators. Lasers Surg.
or noradrenaline, which are as critical as serotonin in depression (Butterweck et al 1997). This suggestion is Dremencov, E., Gur, E., Lerer, B., Newman, M. E. (2003) Effects strengthened by the fact that St John’s wort preferentially of chronic antidepressants and electroconvulsive shock onserotonergic neurotransmission in the rat hippocampus. Prog.
increased extracellular dopamine release in the rat brain Neuropsychopharmacol. Biol. Psychiatry 27: 729–739 using in-vivo microdialysis (Yoshitake et al 2004). In the Hasrat, J. A., De Bruyne, T., De Backer, J. P., Vauquelin, other way, it is reported that acute stress increases seroto- G., Vlietinck, A. J. (1997) Isoquinoline derivatives isolated from nin release (Linthorst et al 1994, 1997; Merali et al 1997; the fruit of Annona muricata as 5-HTergic 5-HT1A receptor Broderick 2002), while chronic stress decreases serotonin agonists in rats: unexploited antidepressive (lead) products.
release in the brain (Meltzer 1989; Risch & Nemeroff 1992; Li et al 2003). Extending the arguments above, the Hjorth, S., Bengtsson, H. J., Kullberg, A., Carlzon, D., Peilot, H., effect of NS on extracellular serotonin concentrations was Auerbach, S. B. (2000) Serotonin autoreceptor function and assessed by microdialysis in rat hippocampus under nor- antidepressant drug action. J. Psychopharmacol. 14: 177–185 mal without any stress or CMS conditions. Our results Jang, C. G., Kang, M., Cho, J. H., Lee, S. B., Kim, H., Park, S., Lee, J., Park, S. K., Hong, M., Shin, M. K., Shim, I. S., Bae, H.
suggest that NS may have an antidepressant effect (2004) Nelumbinis Semen reverses a decrease in 5-HT1A recep- through enhancement of serotonin concentrations, in nor- tor binding induced by chronic mild stress, a depression-like mal without any stress, as well as CMS, conditions. These symptom. Arch. Pharm. Res. 27: 1065–1072 effects are likely mediated by ingredients in NS, such as Kang, M. S. D., Oh, J. W., Cho, C., Lee, H. J., Yoon, D. W., the known neurotransmitter reuptake inhibitor anonaine Lee, S. M., Yun, J. H., Choi, H., Park, S., Shin, M., Hong, M., (Hasrat et al 1997). These results support the development Bae, H. (2005) The anti-depressant effect of Nelumbinis Semen of a novel antidepressant based on the pharmacological on rats under chronic mild stress inducing depression-like action of NS. The molecular mechanism underlying the antidepressant effect of NS requires further study, how- Katz, R. J. (1981) Animal models and human depressive dis- ever, before firm conclusions can be drawn.
orders. Neurosci. Biobehav. Rev. 5: 231–246 Khawaja, X., Xu, J., Liang, J. J., Barrett, J. E. (2004) Proteomic analysis of protein changes developing in rat hippocampus afterchronic antidepressant treatment: implications for depressive disorders and future therapies. J. Neurosci. Res. 75: 451–460 Kim, H., Whang, W. W., Kim, H. T., Pyun, K. H., Cho, S. Y., Hahm, D. H., Lee, H. J., Shim, I. (2003) Expression of neuro- Nelumbinis Semen (NS) through increasing serotonin peptide Y and cholecystokinin in the rat brain by chronic mild concentrations under normal conditions without any stress and reversing a decrease in serotonin concentra- Leitch, M. M., Ingram, C. D., Young, A. H., McQuade, R., tions in rat hippocampus with depression-like symptoms Gartside, S. E. (2003) Flattening the corticosterone rhythm induced by chronic mild stress. NS significantly increased attenuates 5-HT1A autoreceptor function in the rat: relevance serotonin in normal conditions without any stress and for depression. Neuropsychopharmacology 28: 119–125 Li, J. M., Kong, L. D., Wang, Y. M., Cheng, C. H., Zhang, W. Y., reversed a CMS-induced decrease in serotonin release in Tan, W. Z. (2003) Behavioral and biochemical studies on the hippocampus. These results suggest that NS may chronic mild stress models in rats treated with a Chinese increase the serotonin levels normally decreased in traditional prescription Banxia-houpu decoction. Life Sci.
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