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Fructus Aurantii induced antidepressant effect via its monoaminergic mechanism and prokinetic action in rat.


Depression could hardly get a satisfactory effect from the currently available antidepressants. To get a more effective treatment, antidepressant effect and monoaminergic mechanism of Fructus Aurantii (FRA) in the rat forced swimming test (FST) and open field test (OFT), and its prokinetics were examined. FST and OFT were respectively used to evaluate the antidepressant effect and locomotor activity of FRA. We observed the effects of monoamine receptor antagonists on FRA-induced antidepressant effect in rat. The effects of FRA on intestinal transit, gastric emptying and in vitro jejunum contractile activity were assessed. FRA decreased significantly the immobility time (32.6 [+ or -] 8.5, 30.3 15.2 vs 56.4 [+ or -]9.4, all p < 0.01) in FST, dose-dependent increased the locomotor activity (102[+ or -] 17.5, 120[+ or -]18.5 vs 89 1 9.8, p < 0.05 or 0.01), significantly accelerated gastric emptying (GE: 48.1 [+ or -]6.3, 39.5 [+ or -] 5.7 vs 19.5 [+ or -] 3.8, p < 0.01) and intestinal transit (IT: 67.3 [+ or -]9.1, 64.2 [+ or -] 6.3 vs 49.1 [+ or -]8.2, p < 0.01) of the semiliquid meal, compared with vehicle. And FRA (1 [micro]M, 10 significantly increased the mean amplitude (0.24 10.021 and 0.281 10.015) of contraction in jejunum of rat compared with vehicle (0.149 [+ or -] 0.011) in vitro. FRA (10 [micro]M) could induce a largest amplitude (0.281 [+ or -]0.015) of contraction in jejunum. The anti-immobility effect of FRA in EST was prevented by pre-treatment of rat with p-chlorophenylalanine methyl ester, WAY100635, ketanserin, haloperidol, SCH233390, sulpiride, yohimbine, but not prazosin. FRA could simultaneously induce prokinetics and antidepressant effect, deserves further to investigate.

[c] 2012 Elsevier GmbH. All rights reserved.


Keywords: Fructus Aurantii Antidepression Prokinetics Monoaminergic mechanism


Depression, a common mental disorder, will become the second most common cause of disability worldwide by 2020 (Peveler et al. 2002). A large percentage of depressive patients could not get a satisfactory effect from currently available antidepressants with low rates of response and remission. And these drugs are often attended by many side effects (Mai et al. 1993; Kim et al. 2005). For example, selective serotonin reuptake inhibitors (SSR15), as most commonly prescribed antidepressants since mid-1980s, were forced to discontinue because of digestive-tract side effects such as nausea and vomiting (Poyurovsky et al. 1999; Wagstaff et al. 2002; Pigset 1999). These resulted in about 40% of antidepressant invalid, thus a great gap between mechanism and treatment of depression (Kiss 2008) formed.

Noteworthy in this regard is that psychological stimulation elicits delayed gastric emptying, circulating gastrointestinal hormone abnormalities (Zhang et al. 2008; Guo et al. 2001; Liu et al. 2004). Also, depression is often associated with gastrointestinal dysfunction such as abdominal discomfort, nausea, heartburn, bloating, diarrhea and constipation (Zou et al. 2004). Therefore, it is very necessary to develop an antidepressant with prokinetic activity.

Fructus Aurantii (FRA) is the dried immature fruit of Citrus aurantium L. (Rutaceae) and its cultivated variety. Previous study showed that FRA possesses prokinetic, anti-dyspepsia, antiox-idative and anti-inflammatory effects (Huang et al. 2011). FRA as a representative for dispersing stagnated liver qi stagnation in traditional Chinese medicine, has been popularly used for relieving depression-like symptoms such as pain, insomnia, sad and depressed for more than 2000 years. According to these, we proposed a hypothesis "Chinese medicine or herbs for regulating qi-flowing or relieving qi stagnation often has antidepressant and gastroprokinetic effects". Therefore, we evaluated FRA's antidepression by the OFT and FST, and gastroprokinetic by the measurements of the gastric emptying and gastrointestinal transit and in vitro jejunum contractile activity in rats. To verify the effect of FRA's antidepression over serotonergic, noradrenergic and dopaminergic system, the anti-immobility effect of FRA in FST was prevented by pre-treatment of rat with their receptor antagonists.

Materials and methods


Male Sprague Dawley rats (Changsha, China), weighing 160-200g, were housed under standardized environmental conditions (20-22 [degrees]C, 12 h light/dark cycle with light on at 6.30 a.m., 50 [+ or -] 10% relative humidity), with free access to food and water. All experimental procedures were conducted in accordance with the Regulations for the Administration of Affairs Concerning Experimental Animals (1988) and approved by the Animal Experimental Center for Central South University.

Preparation of FRA and quantitative analysis of main components

Preparation of FRA

Fructus Aurantii (FRA) granula was purchased from China Resources Sanjiu Medical & Pharmaceutical Co., Ltd. It was extracted by 70% ethanol. In short, the materials (100g) are extracted twice with 5-fold volumes of 70% ethanol (500 ml) at 70 [degrees]C for 1 h each time. Then the supernatant, after centrifuging at 2000 g, is pooled and lyophilized to make a powder with 22.8% yields for FRA.

Sample preparation

For UPLC analysis the lyophilized powder was dissolved in distilled water, the amount dissolved being equivalent to 15 mg FRA [m1.sup.-1] water. All solutions were filtered through a 0.45 [micro]m pore size filter before analysis. The injection volume was 3 [micro]l, FRA's concentration in each decoction before injection is 0.31 mg/ml.


A Waters Acquity UPLC BEH 2.1 mm x 100 mm, 1.7 [micro]m C18 column system (Waters Corporation, USA) was used to analyze. The system consisted of a quaternary pump solvent management system, an on-line degasser and an autosampler. The raw data were detected, acquired and processed with Empower Software.

Chromatographic conditions

The mobile phase was acetonitrile -0.5% aqueous acetic acid with gradient elution (0 min, 13:100; 10 min, 18:100; 20 min, 25:100; 25 min, 60:100). The components were quantified based on peak areas at the maximum wavelength in their UV spectrum.

Preparation of standard solutions

A standard stock solution of each of the 5 components and their standard solutions were directly prepared and diluted with methanol to establish calibration curves. All were prepared in dark brown calibrated flasks and stored at 4 [degrees]C. The linearity of the responses was determined for seven concentrations. The standard curves from the peak area of each compound were prepared by Empower software. Their contents in the test samples were calculated by the regression parameters obtained from the standard curves respectively.

Quantitative analysis results

The contents of main components in the 70% ethanol extracts of FRA are determined by Ultra Performance Liquid Chromatography (UPLC) as 2.8% of Naringin, 6.3% of Hesperidin, 8.6% of Narirutin, 6.7% of Neohesperidin, 4.5% of Merazin hydrate (Fig. 1).

Drug administration

The following drugs were used: prazosin Hydrochloride, yohimbine hydrochloride, ketanserin, p-chlorophenylalanine (PCPA), haloperidol, sulpiride, WAY100635, SCH23390, Fluoxetine, Mosapride, Evans blue, methylcellulose (all from Sigma Chemical Co., St. Louis, U.S.A.). Sulpiride and prazosin were diluted in saline with 5% dimethyl-sulfoxide (DMSO). Ketanserin, prazosin, yohimbine, propranolol and sulpiride were administered by intraperitoneal (i.p.) route. SCH23390 and WAY100635 were administered by subcutaneous (s.c.) route.

Fructus Aurantii (FRA) granula was purchased from China Resources Sanjiu Medical & Pharmaceutical Co., Ltd. All drugs were dissolved in distilled water and administered in a constant volume of 10 ml/kg body weight (Kim et al. 2005; Aynara et al. 2010). FRA (3, 9 or 18 mg/kg, p.o.), Fluoxetine (20 mg/kg, p.o.) and their Vehicle (1.5 ml saline, p.o.) were administered half an hour before the behavior test. The cut crude drug of FRA of 3, 9 or 18 mg is equivalent to 0.68 g, 2 g and 4 g of FRA granula respectively. Appropriate vehicle-treated groups were also assessed simultaneously.

In the experiments designed to study the time-course effect of FRA (18 g/kg), the immobility time in FST was assessed in an independent group of rat, 0.5 h, 1 h, 2 h and 4 h after the administration of FRA (Posser et al. 2009). To investigate the influence of the serotonergic system in the antidepressant effect of FRA, rats were pretreated with PCPA (100 mg/kg, i.p., an inhibitor of serotonin synthesis) or vehicle once a day for 3 days. Then, 24h after the last PCPA injection, FRA was given orally to rats. 30 min later, rats were tested in FST for 5 min. And the involvement of the 5-HT receptor subtypes, the noradrenergic and the dopaminergic systems in the effect of FRA in FST were also studied. Rats were pretreated with WAY100635 (0.1 mg/kg, s.c., a selective 5-HT1A receptor antagonist), ketanserin (5 mg/kg, i.p., a preferential 5-HT2A receptors antagonist), prazosin (1 mg/kg, i.p., an [alpha]1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an [alpha]2-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D1 receptor ant agonist) or sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist), or vehicle and after 30 min, received FRA (18 g/kg, p.o.) or vehicle injection before being tested 30 min later.

Open-field test (OFT)

Each rat was individually placed into the center of the open field apparatus (40 cm height, 77 cm x 77 cm base divided into 49 squares 11 cm x 11 cm each) to measure the locomotor activity for 5 min. The test was performed between 9:00 and 12:00. A 60W light bulb was positioned 90-100 cm above the center, and provided the only source of illumination in the testing room. The measurement parameters included the number of times the animal crossed any square. A rat stepping from one square to another with its rear legs was considered a square crossing. The square chamber was cleaned each time after testing a rat.

Forced swimming test (FST)

The anti-depression action by FRA was assessed by FST. The rats were individually forced to swim twice at 24-h intervals in a cylinder (40 cm high, 18 cm in diameter) filled with water (25 [degrees]C) up to 30 cm. A 15-min preswimming period was followed 24-h later by a 5-min test period during which scoring was done by two independent observers blind to the treatment conditions. The behavior was scored every 5 s based on the criteria listed below. Each rat was judged to be immobile when it ceased struggling and remained floating motionless in the water, making only those movements necessary to keep its head above water (Porsolt et al. 1977a).

In vivo measurements of gastrointestinal motility

A protocol was adapted from De Winter et al. (1999, 2002, 2004) (De Schepper et al. 2007). Gastric emptying was determined spectrophoto-metrically, the method was adapted from De Winter et al. (2004) (Lange et al. 1994).

Measurement of contractile activity

After just a 24-h fast, rats were sacrificed by cervical dislocation, and segments of the proximal jejunum were quickly removed and placed in Krebs-bicarbonate buffer (118 mM NaCl, 4.8 mM KCl, 1.2 mM [KH.sub.2][PO.sub.4], 1.2 mM [MgSO.sub.4], 2.5 mM [CaCl.sub.2], 25 mM [NaHCO.sub.3] and 11 mM Glucose, pH 7.4, at 37 [degrees]C). A 1.5-cm jejunal segment was mounted in 5 ml organ bath chambers containing continuously oxygenated (5% [C.O.sub.2], 95% [0.sub.2]) modified Krebs-Ringer buffer. The temperature was maintained at 37[degrees]C. The lower end of the tissue segments was anchored to the bottom of the chamber and the other end connected to a transducer. The contractile responses of the segments to FRA were measured according to Cheng et at. (2010) (Huang et al. 2011). FRA was administered at increasing concentrations (1-100 [micro]M) without washing between the administrations. The mean amplitude was measured for each concentration in the same way.


Behavioral effects of FRA on OFT and FST

FRA (9, 18 g/kg) similar to Fluoxetine (20 mg/kg) produced a significant dose-dependent increase in locomotor activity ( 1 02 [+ or -] 17.5, 120 [+ or -] 18.5, 115 [+ or -] 19.2 vs 89 [+ or -] 9.8, p < 0.05 or 0.01) of rats in OFT (p < 0.01, Fig. 2), decreased significantly the immobility time (32.6[+ or -] 8.5, 30.3 [+ or -] 5.2, 43.3 [+ or -] 8.7) compared with vehicle (vs 56.4 [+ or -] 9.4, all p <0.01) in FST (Fig. 3).

Time-course analysis

In order to investigate the interval time that FRA the best performance in FST, a time-response curve was carried out (Fig. 4).

The SD rats were tested in the forced swimming test 0.5 h, 1 h, 2 h and 4 h after the administration of FRA in independent groups. FRA exerted antidepressant activity in the forced swimming test as early as 30 min after administration, the effect that remained statistically significant (immobility time (s): 35.9 [+ or -] 4.8 and 57.4 [+ or -] 8.2 vs 68.3 [+ or -] 12.4, p < 0.01 and 0.05 respectively) until 2 h after drug administration.

Involvement of the serotonergic, noradrenergic and dopaminergic system in the antidepressant effect of FRA in FST

The dose of 18 g/kg FRA was chosen for the investigation of participation of the monoaminergic system in its antidepressant action in FST. The results showed anti-immobility effect of FRA were significantly prevented by pretreatment of rat with 5HT receptor antagonist (PCPA, WAY100635 and ketanserin (Fig. 5), dopamine receptor antagonist (haloperidol, SCH23390, sulpiride) (Fig. 7), and [alpha]2-adrenoceptor (yohimbine) (all p < 0.01, Fig. 6A), but not prazosin (p > 0.05, Fig. 6B).

Gastric emptying and Small intestinal transit

Compared to Vehicle, FRA (9 or 18g/kg) and Mosapride (10 mg/kg) significantly accelerated gastric emptying (GE: 19.51-3.8 vs 48.1 [+ or -]6.3, 39.5 [+ or -] 5.7, 34.8 [+ or -] 6.1) and intestinal transit (IT: 49.1 [+ or -]8.2 vs 67.3 [+ or -] 9.1, 64.2 [+ or -] 6.3, 60.1 [+ or -] 9.5) of the semi-liquid meal (p <0.01, Fig. 8), while Fluoxetine (20 mg/kg) significantly decelerated them (GE: 13.1 [+ or -]2.5 vs 19.5 [+ or -]3.8, p <0.01; IT: 40.5 [+ or -] 6.3, p <0.05).

Fig. 9 showed that FRA (1[micro]M, 10 [micro]M) significantly increased the mean amplitude (0.24 [+ or -] 0.021 and 0.281 [+ or -] 0.015) of contraction in jejunum of rat compared with vehicle (0.149[+ or -]0.011) in vitro. FRA (10 [micro]M) could induce a largest amplitude (0.281 [+ or -]0.015) of contraction in jejunum. However, FRA (100 [micro]M) significantly decreased it, which was 0.058 [+ or -] 0.0012.


Study showed that FRA administered orally could induce a significant decrease in the immobility time in FST, a significant increase in locomotor activity of rats in OFT. FRA exerted antidepressant activity in FST as early as 30 min after administration, the effect that remained statistically significant until 2 h after drug administration, disappeared until 4 h. Also, the antidepressive action may be dependent on the serotonergic, noradrenergic and dopaminergic systems. In addition, FRA (9 or 18 g/kg) and Mosapride (10 mg/kg), different from Fluoxetine (20 mg/kg), significantly accelerated gastric emptying and intestinal transit. And FRA's prokinetics was supported by the jejunum contraction test in vitro.

The main components of FRA granula are naringin, hesperidin, neohesperidin, narirutin and meranzin hydrate by UPLC. Narirutin, hesperidin, neohesperidin and Naringin belong to Flavonoids. Previous studies have demonstrated that the total flavonoids reversed behavioral alterations and serotonergic dysfunctions in chronically stressed rats (An et al. 2008). Study also showed that Naringin could significantly attenuate neurobehavioral alterations by removing free radicals (Aggarwal et al. 2010). Meranzin hydrate, a novel anti depression and prokinetic compound, was first separated and identified by UV, RI, MS and NMR from FRA in our recently unpublished work. Study proved Meranzin hydrate and hesperidin could promote the gastrointestinal movement, may be main prokinetic compounds of FRA (Qiu et al. 2011; Fang et al. 2009). Therefore, FRA's antidepressive and prokinetic actions may be synergistically responsible by Narirutin, hesperidin, neohesperidin, Naringin, Meranzin hydrate and by Meranzin hydrate and hesperidin respectively.

Most antidepressants such as SSRIs are poorly tolerated because of adverse side effects (Guadarrama-Cruz et al. 2008). This leads to a low success rate (less than 60%) of medication, means at least 40% of the patients do not respond to the initial treatment (Kiss 2008; Nestler et al. 2002). FRA's antidepressive and prokinetic actions could bring a better treatment, make up for inhibition of gastric motor activity of SSRIs (Kim et al. 2006; Zhang et al. 2011).

FST and OFT are two paradigms used for evaluating the effect of drugs on gross general behavior (File and Fernandes 1994). They are also quite sensitive and relatively specific to all major classes of antidepressants including tricyclics, serotonin-specific reuptake inhibitors, monoamine oxidase inhibitors, and atypical (Porsolt et al. 1977b; Cryan and Lucki 2000; Cryan et al. 2002). In the present study, statistically significant results were obtained in OPT and FST with treatment of FRA at 9 g/kg and 18 g/kg (the former: 15% and 35% increase; the latter: 42% and 46% reduction respectively), similar with Fluoxetine (29.2% increase and 23% reduction). FRA at 3 g/kg has very little antidepressant action. The highest dose of FRA shows comparable effect as fluoxetine in terms of its antidepressant actions. FRA induced the best antidepressant effect in FST as early as 30 min, which disappeared until 2 h after administration. These also show FRA antidepressant treatment has time-and dose-dependent effects.

Abnormalities of central nervous system metabolism and function, involving the monoamine neurotransmitters, play an important role in the pathogenesis of depression (Coppen 1967; Schildkraut 1965). Serotonin, noradrenaline and dopamine (DA) are major targets for currently available antidepressant drugs (Nitta et al. 1992). Tricyclics, such as imipramine, block the reuptake of noradrenaline, dopamine, and serotonin causing an increase in the level of these neurotransmitters in the presynaptic membrane (Zhou et al. 2007; O'Leary et al. 2007). MAOls work by blocking the enzyme monoamine oxidase which breaks down the monoamine neurotransmitters (Smith et al. 1996).

Study results indicate that the serotonin (5-HT) system is strongly implicated in the neural regulation of mood and several pieces of evidence have implicated abnormalities in 5-HT neurotransmission in the pathophysiology of depression (Wong and Licinio 2001). The system has been recognized as playing an important role in the etiology of depression. Drugs acting on the serotonergic system have been largely implicated in the treatment of depressive disorders (Blier and Ward 2003; Elhwuegi 2004).

The noradrenergic system is crucial in the pathophysiology of depression (George et al. 2006). Depression was also associated with a hypofunction of the noradrenergic system (Blier and Ward 2003). Eighteen or 72% of the antidepressants were more potent at blocking uptake of norepinephrine than that of serotonin (RicheIson and Pfenning 1984).

Dopamine (DA) is also involved in the pathophysiology and treatment of depression (Nitta et al. 1992). A deficiency of mesolimbic dopamine (DA) is a leading candidate for the etiology of certain symptoms of depression. Studies suggest that the dopaminergic system may play a major role in the pathophysiology of depression. Disturbances in dopaminergic neurotransmission seem to mediate the biochemical mechanisms involved in depressive disorders (Pitchot et al. 1993). Furthermore, some substances that modulate the dopaminergic system are being used as antidepressants, such as bupropion (Dhillon et al. 2008). It is well established that the increase in central dopaminergic transmission regulates the neuronal activity of 5-1-IT and noradrenaline (Guiard et al. 2009).

Our study showed that the anti-immobility effect of FRA was prevented by pretreatment of rat with PCPA, WAY100635, ketanserin, yohimbine, haloperidol, SCH23390 and sulpiride, but no prazosin in FST, providing evidence of the participation of 5-HT1A and 5-HT2A receptor antagonist, a2-adrenoceptor antagonist, D1 and D2 receptor antagonist but not al-adrenoceptor antagonist in the antidepressant-like effect of FRA in the rat FST. However, our behavioral results do not allow us to conclude about the mechanism by which FRA may affect the synaptic levels of monoamines, thus further studies about the relation between FRA treatment and serotonin, noradrenaline, and dopamine levels are needed to clarify this issue.

In inclusion, FRA as a desirable antidepressant deserved further investigation, because it possessed both antidepressant via monoaminergic system and gastroprokinetic effects. Evidence supported the hypothesis "Chinese medicine or herbs for regulating qi-flowing or relieving di stagnation often have both antidepressant and gastroprokinetic effect".


This work was supported by a grant (No. 81072967; No. 81173591) from Natural Science Foundation of China, the fund for Key Laboratory of TCM Gan of SATCM, National Key Clinical Specialist Vocational School of TCM Encephalopathy, and partly supported by The Natural Science Innovation Group Foundation of Hunan Province (12JJ7006).

Abbreviations: FRA, Fructus Aurantii; FST, forced swimming test; OFT, open field test; FD, functional dyspepsia; IBS, irritable bowel syndrome.


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* Corresponding author at: Institute of Integrated Traditional Medicine and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.

E-mail address: tcmhuangx59@1 (X. Huang).

0944-7113/$-see front matter 2012 Elsevier GmbH. All rights reserved.

Ying-jin Zhang (a), (b), Wei Huang (a), (c), Xi Huang* (a), (c), (d), Yang Wang (a), (c), Zhe Wang (b), Cheng Wang (e), Bing-wu Zhong (b), Chen-xia Sheng (b), Bing Wang (b), Si-fang Zhang (b), Nan-xiang Su (b), Zhao-qian Liu (d), Hong-hao Zhou (d), Ping Ren (a), (c)

(a) Laboratory of Ethnopharmacology, Institute of Integrated Traditional Medicine and Western Medicine, Xiangya Hospital, Central South University, Changsha 410008, China

(b) Department of traditional chinese medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China

(c) National Key Clinical Specialist Vocational School of TCM Encephalopathy, Xiangya Hospital, TCM Pharmacogenetics Laboratory, Central South University, Changsha 410008, China

(d) Instutite of Clinical Pharmacolgy, Central South University, Changsha 410008, China

(e) Institute of Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Author:Zhang, Ying-jin; Huang, Wei; Huang, Xi; Wang, Yang; Wang, Zhe; Wang, Cheng; Zhong, Bing-wu; Sheng, C
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Geographic Code:9CHIN
Date:Sep 15, 2012
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