Citrus aurantium L. essential oil exhibits anxiolytic-like activity mediated by 5-HT1A-receptors and reduces cholesterol after repeated oral treatment

BMC Complementary and Alternative Medicine

Mirtes Costa¹  Jorge C Flório²  Regina K Takahira³  Bruna O Cassettari¹  Thaís C Cury¹  Celso A R A Costa¹ 

[1] Department of Pharmacology, Institute of Biosciences, Unesp - Univ Estadual Paulista, P.O. Box 510, 18618-970, Botucatu, São Paulo, Brazil;Department of Pathology, School of Veterinary Medicine, USP - University of São Paulo, Av. Orlando Marques de Paiva, 87, São Paulo, SP, Brazil;Department of Pathology, School of Veterinary Medicine and Animal Science, Unesp - Univ Estadual Paulista, Laboratório Clínico Veterinário, 18618-970, Botucatu, SP, Brazil

关键词: Serotonin;    Neurochemistry;    Mice;    Essential oil;    Citrus aurantium;    Anxiolytic;   

Others  :  1230972
DOI  :  10.1186/1472-6882-13-42

 received in 2012-09-11, accepted in 2013-02-11,  发布年份 2013

【 摘 要 】

Background

The current treatments for anxiety disorders and depression have multiple adverse effects in addition to a delayed onset of action, which has prompted efforts to find new substances with potential activity in these disorders. Citrus aurantium was chosen based on ethnopharmacological data because traditional medicine refers to the Citrus genus as useful in diminishing the symptoms of anxiety or insomnia, and C. aurantium has more recently been proposed as an adjuvant for antidepressants. In the present work, we investigated the biological activity underlying the anxiolytic and antidepressant effects of C. aurantium essential oil (EO), the putative mechanism of the anxiolytic-like effect, and the neurochemical changes in specific brain structures of mice after acute treatment. We also monitored the mice for possible signs of toxicity after a 14-day treatment.

Methods

The anxiolytic-like activity of the EO was investigated in a light/dark box, and the antidepressant activity was investigated in a forced swim test. Flumazenil, a competitive antagonist of benzodiazepine binding, and the selective 5-HT_1A receptor antagonist WAY100635 were used in the experimental procedures to determine the mechanism of action of the EO. To exclude false positive results due to motor impairment, the mice were submitted to the rotarod test.

Results

The data suggest that the anxiolytic-like activity observed in the light/dark box procedure after acute (5 mg/kg) or 14-day repeated (1 mg/kg/day) dosing was mediated by the serotonergic system (5-HT_1A receptors). Acute treatment with the EO showed no activity in the forced swim test, which is sensitive to antidepressants. A neurochemical evaluation showed no alterations in neurotransmitter levels in the cortex, the striatum, the pons, and the hypothalamus. Furthermore, no locomotor impairment or signs of toxicity or biochemical changes, except a reduction in cholesterol levels, were observed after treatment with the EO.

Conclusion

This work contributes to a better understanding of the biological activity of C. aurantium EO by characterizing the mechanism of action underlying its anxiolytic-like activity.

【 授权许可】

   
2013 Costa et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]López-Muñoz F, Alamo C, García-García P: The Discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. J Anx Disord 2011.
• [2]Ravindran LN, Stein MB: The pharmacologic treatment of anxiety disorders: a review of progress. J Clin Psychiaty 2010, 71(Suppl 7):839-854.
• [3]Uzun S, Kozumplik O, Jakovljević M, Sedić B: Side effects of treatment with benzodiazepines. Psych Danub 2010, 22(Suppl 1):90-93.
• [4]Barret JE, Vanover KE: 5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions. Psychopharmacology 1993, 112:1-12.
• [5]Lowry CA, Johnson PL, Hay-Schmidt A, Mikkelsen J, Shekhar A: Modulation of anxiety circuits by serotonergic systems. Stress 2005, 8:233-246.
• [6]Mitchell AJ: Two-week delay in onset of action of antidepressants: new evidence. B J Psych 2006, 188:105-106.
• [7]Halfin A: Depression: the benefits of early and appropriate treatment. Am J Manag Care 2007, 13:S92-S97.
• [8]Hamon M, Bourgoin S: Pharmacological profile of antidepressants: a likely basis for their efficacy and side effects? Eur Neuropsychopharm 2006, 16:S625-S632.
• [9]Cryan JF, Holmes A: The ascent of mouse: advances in modeling human depression and anxiety. Nat Rev Drug Discov 2005, 4(Suppl 9):775-790.
• [10]Pilc A, Nowak G: GABA-ergic hypotheses of anxiety and depression: Focus on GABA-B receptor. Drugs Today (Barc) 2005, 41(Suppl 11):755-766.
• [11]Hernandez L, Munoz RA, Miro G, Martinez M, Silva-Parra J, Chaves PI: Use of medicinal plants by ambulatory patients in Puerto Rico. Am J Hosp Pharm 1984, 41:2060-2064.
• [12]Girón LM, Freire V, Alonzo A, Cáceres A: Ethnobotanical survey of the medicinal flora used by the Caribs of Guatemala. J Ethnopharmacol 1991, 34:173-187.
• [13]Tortoriello J, Romero O: Plants used by Mexican tradicional medicine with presumable sedative properties: an ethnobotanical approach. Arch Med Res 1992, 23:111-116.
• [14]Longuefosse JL, Nossin E: Medical ethnobotany survey in Martinique. J Ethnopharmacol 1996, 53:117-142.
• [15]Vásquez FM, Suarez MA, Pérez A: Medicinal plants used in the Barros Área, Badajoz province (Spain). J Ethnopharmacol 1997, 55:81-85.
• [16]Leite MP, Fassin-Jr J, Baziloni EMF, Almeida RN, Mattei R, Leite JR: Behavioral effects of essential oil of Citrus aurantium L. inhalation in rats. Braz J Pharmacogn 2008, 18:661-666.
• [17]Saiyudthong S, Marsden CA: Acute effects of bergamot oil on anxiety-related behaviour and corticosterone level in rats. Phytoterapy Research 2011, 25:858-862.
• [18]Lehner J, Eckersberger C, Walla P, Pötsch G, Deecke L: Ambient odor of orange in a dental office reduces anxiety and improves mood in female pacients. Physiol Behav 2000, 71:83-86.
• [19]Akhlaghi M, Shabanian G, Rafieian-Kopaei M, Parvin N, Saadat M, Akhlaghi M: Citrus aurantium Blossom and Preoperative Anxiety. Rev Bras Anestesiol 2011, 61(6):702-712.
• [20]Potdar VH, Kibile SJ: Evaluation of Antidepressant-like Effect of Citrus Maxima Leaves in Animal Models of Depression. Iran J Basic Med Sci 2011, 14(5):478-483.
• [21]Campelo LML, Sa CG, de Almeida AAC, Costa JP, Marques THC, Feitosa CM, Saldanha GB, Freitas RM: Sedative, anxiolytic and antidepressant activities of Citrus limon (Burn) essential oil in mice. Pharmazie 2011, 66(8):623-627.
• [22]Komori T, Fujiwara R, Tanida M, Nomura J, Yokoyama MM: Effects of Citrus fragrance an immune function and depressive states. Neuroimmunomodulation 1995, 2(3):174-180.
• [23]Carvalho-Freitas MIR, Costa M: Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biol Pharm Bull 2002, 25(Suppl 12):1629-1633.
• [24]Pultrini AM, Galindo LA, Costa M: Effects of the essential oil from Citrus aurantium L. in experimental anxiety models in mice. Life Sciences 2006, 78:1720-1725.
• [25]Gargano AC, Costa CARA, Costa M: Essential oils from Citrus latifolia and Citrus reticulate reduces anxiety and prolong ether sleeping time in mice. Tree For Sci Biotech 2008, 2(Suppl 1):121-124.
• [26]Graeff FG, Zangrossi H Jr: Animal models of anxiety disorders. In Biological Psychiatry. Edited by D’Haenen H, den Boer JA, Willner P. West Sussex: John Wiley and Sons; 2002:96-103.
• [27]Ichimaru Y, Egawa T, Sawa A: 5-HT1A Receptor subtype mediates the effect of fluvoxamine, a selective serotonin reuptake inhibitor, on marble-burying behavior in mice. Jap J Pharmacol 1995, 68:65-70.
• [28]Costa CARA, Köhn DO, Lima VM, Gargano AC, Flório JC, Costa M: The GABAergic system contributes to the anxiolytic-like effect of essential oil from Cymbopogon citratus (lemongrass). J Ethnopharmacol 2011, 137:828-836.
• [29]Crawley J, Goodwin FK: Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharmacol Biochem Behav 1980, 13:167-170.
• [30]Bourin M, Hascoët M: The mouse light/dark box test. Eur J Pharmacol 2003, 463:55-65.
• [31]Young R, Johnson DN: A fully automated light/dark apparatus useful for comparing anxiolytic agents. Pharmacol Biochem Behav 1991, 40:739-743.
• [32]Davidson J, Feltner D, Dugar A: Management of Generalized Anxiety Disorder in Primary Care: Identifying the Challenges and Unmet Needs. Prim Care Companion J Clin Psychiatry 2010, 12(2):PCC.09r00772.
• [33]Dunham NW, Miya TS: A note on a simple apparatus for detecting neurological deficit in rats and mice. JAMA 1957, 46:208-209.
• [34]Petit-Demouliere B, Chenu F, Bourin M: Forced swimming test in mice: a review of antidepressant activity. Psychopharmacology 2005, 177:245-255.
• [35]Porsolt RD, Bertin A, Jalfre M: Behavioural despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn 1977, 229:327-336.
• [36]Cryan JF, Markou A, Lucki I: Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 2002, 23:238-245.
• [37]Ottoni EB: EthoLog2.2 - A tool for the transcription and timing of behavior observation sessions. Behav Res Meth Instr Comp 2000, 32(Suppl 3):446-449.
• [38]Almeida RN, Motta SC, Brito FC, Catallani B, Leite JR: Anxiolytic like effects of rose oil inhalation on the elevated plus maze test in rats. Pharmacol Biochem Behav 2004, 77:361-364.
• [39]Felício LF, Flório JC, Sider LH, Cruz-Casallas PE, Bridges RS: Reproductive experience increases striatal and hypothalamic dopamine levels in pregnant rats. Brain Res Bull 1996, 40:253-256.
• [40]Adams RP: Identification of essential oil components by gas chromatography/mass spectroscopy. Carol Stream, Illinois: Allured; 2007.
• [41]Kalueff AV, Wheaton M, Murph DL: What’s wrong with my mouse model? Advances and strategies in animal modeling of anxiety and depression. Behav Brain Res 2007, 179:1-18.
• [42]Kendler KS, Heath AC, Martin NG, Eaves LJ: Symptoms of anxiety and symptoms of depression: same genes, different environments? Arch Gen Psychiatry 1987, 7:445-451.
• [43]Vale TG, Furtado EC, Santor JG Jr, Viana GSB: Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) N. E. Brown. Phytomedicine 2002, 9:709-714.
• [44]Galindo LA, Pultrini AM, Costa M: Biological effects of Ocimum gratissimum L. are due to synergic action among multiple compounds present in essential oil. J Nat Med 2010, 64:436-441.
• [45]Toth M: Use of Mice with Targeted Genetic Inactivation in the Serotonergic System for the Study of Anxiety. In Serotonin Receptors in Neurobiology. Edited by Chattopadhyay A. Boca Raton (FL): CRC Press; 2007.
• [46]Vandenberg LN, Colborn T, Hayes TB, Heindel JJ, Jacobs DR Jr, Lee D-H, Shioda T, Soto AM, Saal FS, Welshons WV, Zoeller RT, Myers JP: Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses. Endocr Rev 2012, 33(3):378-455.
• [47]Calabrese EJ: An assessment of anxiolytic drug screening tests: hormetic dose responses predominate. Crit Rev Toxicol 2008, 38:489-542.
• [48]Conolly RB, Lutz WK: Nonmonotonic Dose-response Relationships: Mechanistic Basis, Kinetic Modeling, and Implications for Risk Assessment. Toxicol Sci 2004, 77:151-157.
• [49]Komiya M, Takeuchi T, Harada E: Lemon oil vapor causes an anti-stress effect via modulating the 5-HT and DA activities in mice. Behav Brain Res 2006, 172:240-249.
• [50]Lucki I, Singh A, Kreiss DS: Antidepressant-Like Behavioral Effects of Serotonin Receptor Agonists. Neurosci Behav Rev 1994, 18:85-95.
• [51]Arbo MD, Schmitt GC, Limberger MF, Charão MF, Moro AM, Ribeiro GL, Dallegrave E, Garcia SC, Leal MB, Limberger RP: Subchronic toxicity of Citrus aurantium L. (Rutaceae) extract and p-synephrine in mice. Reg Toxicol Pharmacol 2009, 54:114-117.
• [52]Kurowska EM, Manthey JA: Hypolipidemic effects and absorption of Citrus polymethoxylated flavones in hamsters with diet-induced hypercholesterolemia. J Agric Food Chem 2004, 52:2879-2886.
• [53]Santiago JVA, Jayachitra J, Shenbagam M, Nalini N: d-limonene attenuates blood pressure and improves the lipid and antioxidant status in high fat diet and L-NAME treated rats. J Pharm Science Res 2010, 2(Suppl 11):752-758.