Share This Article:

Melatonin and Diazepam Affect Anxiety-Like and Depression-Like Behavior in Wistar Rats: Possible Interaction with Central GABA Neurotransmission

Abstract Full-Text HTML Download Download as PDF (Size:200KB) PP. 522-533
DOI: 10.4236/jbbs.2013.37055    3,151 Downloads   5,533 Views   Citations


Recent studies have shown the importance of the GABA-ergic transmission in the pathophysiology of anxiety and depressive disorders in humans. Our present study aims to investigate the interaction of melatonin (MEL) with this system by exploring the effects of MEL with or without a facilitator of GABA-ergic neurotransmission, diazepam (DZ) on the levels of depression and anxiety in Wistar rats. For this purpose, different doses of MEL (2, 4 or 16 mg/kg) or DZ (2 mg/kg) are subchronically administered during 15 days. After pharmacological treatments, anxiety levels are evaluated in behavioral tests of Open Field (OFT) and elevated plus maze (EPM) and depression levels are evaluated by the forced swim test (FST). The results showed that MEL produces anxiolytic-like and antidepressant-like effects in a dose-dependent manner; the maximum effect was obtained at a dose of 16 mg/kg. However, a dose of 4 mg/kg is necessary to induce an effect. The effect of MEL and DZ reported in this study concerns selective modulation of behavioral anxiety and depression since locomotor activity assessed by the OFT and EPM was not affected. The subchronic injection of MEL at 4 mg/kg, DZ at 2 mg/kg or the two combined molecules also induces also anxiety-like and antidepressant-like behavior. In addition, a potentiating effect between MEL and DZ was observed. These effects suggest that psychopharmacological actions of MEL are due, at least in part, to its ability to improve the central GABA-ergic transmission.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

S. Ouakki, F. Mrabet, I. Lagbouri, A. Hessni, A. Mesfioui, P. Pévet, E. Challet and A. Ouichou, "Melatonin and Diazepam Affect Anxiety-Like and Depression-Like Behavior in Wistar Rats: Possible Interaction with Central GABA Neurotransmission," Journal of Behavioral and Brain Science, Vol. 3 No. 7, 2013, pp. 522-533. doi: 10.4236/jbbs.2013.37055.


[1] R. A. Hoffman and R. J. Reiter, “Rapid Pinealectomy in Hamsters and Other Small Rodents,” The Anatomical Record, Vol. 24, No. 1, 1965, pp. 83-89.
[2] H. Illnerova, J. Vaneek and K. Hoffmann, “Regulation of the Pineal Melatonin Concentration in the Rat (Rattus norvegicus) and the Djungarian hamster (Phodopus sungorus),” Comparative Biochemistry and Physiology, Vol. 74, No. 1, 1983, pp. 155-159.
[3] J. Leston, C. Harthé, J. Brun, C. Mottolese, P. Mertens, M. Sindou and B. Claustrat, “Melatonin Is Release in the Third Ventricle in Humans. A Study in Movement Disorders,” Neuroscience Letters, Vol. 469, No. 3, 2009, pp. 294-297.
[4] B. Claustrat, J. Brun and G. Chazot, “The Basic Physiology and Pathophysiology of Melatonin,” Sleep Medicine Reviews, Vol. 9, No. 1, 2005, pp. 11-24.
[5] P. Pevet, “The Role of the Pinealgland in the Photoperiodic Control of Reproduction in Different Hamster Species,” Reproduction Nutrition Development, Vol. 28, No. 2B, 1988, pp. 443-458.
[6] R. Brown, J. H. Kocsis, S. Caroff, J. Amsterdam, A. Winokur, P. E. Stokes and A. Frazer, “Differences in Nocturnal Melatonin Secretion between Melancholic Depressed Patients and Control Subjects,” American Journal of Psychiatry, Vol. 142, No. 7, 1985, pp. 811-816.
[7] I. M. McIntyre, T. R. Norman, G. D. Burrows and S. M. Armstrong, “Melatonin, Cortisol and Prolactin Response to Acute Nocturnal Light Exposure in Healthy Volunteers,” Psychoneuroendocrinology, Vol. 17, No. 2-3, 1992, pp. 243-248.
[8] B. Bandelow, G. Sengos, D. Wedekind, G. Huether, J. Pilz, A. Broocks, G. Hajak and E. Ruther, “Urinary Excretion of Cortisol, Norepinephrine, Testosterone, and Melatonin in Panic Disorder,” Pharmacopsychiatry, Vol. 30, No. 4, 1997, pp. 113-117.
[9] R. G. Lister, “Ethologically-Based Animal Models of Anxiety Disorders,” Pharmacology & Therapeutics, Vol. 46, No. 3, 1990, pp. 321-340.
[10] C. Kopp, E. Vogel, M. C. Rettori, P. Delagrange, B. Guardiola-Lemaitre and R. Misslin, “Effects of Melatonin on Neophobic Responses in Different Strains of Mice,” Pharmacology Biochemistry and Behavior, Vol. 63, No. 4, 1999, pp. 521-526.
[11] C. Kopp, E. Vogel, M. C. Rettori, P. Delagrange and R. Misslin, “Anxiolytic-Like Properties of Melatonin Receptor Agonists in Mice: Involvement of Mt1 and/or MT2 Receptors in the Regulation of Emotional Responsiveness,” Neuropharmacology, Vol. 39, No. 10, 2000, pp. 1865-1871.
[12] F. Z. El Mrabet, I. Lagbouri, A. Mesfioui, A. El Hessn and A. Ouichou, “The Influence of Gonadectomy on Anxiolytic and Antidepressant Effects of Melatonin in Male and Female Wistar Rats: A Possible Implication of Sex Hormones,” Neuroscience & Medicine, Vol. 3, No. 2, 2012, pp. 162-173.
[13] F. Z. El Mrabet, S. Ouakki, A. Mesfioui, A. El Hessni and A. Ouichou, “Pinealectomy and Exogenous Melatonin Regulate Anxiety-Like and Depressive-Like Behaviors in Male and Female Wistar Rats,” Neuroscience & Medicine, Vol. 3, 2012, pp. 394-403.
[14] B. Guardiola-Lemaitre, A. Lenegre and R. D. Porsolt, “Combined Effects of Diazepam and Melatonin in Two Tests for Anxiolytic Activity in the Mouse,” Pharmacology Biochemistry and Behavior, Vol. 41, No. 2, 1992, pp. 405-408.
[15] A. Pilc and K. G. Lloyd, “Chronic Antidepressants and GABA “B” Receptors: A GABA Hypothesis of Antidepressant Drug Action,” Life Sciences, Vol. 35, No. 21, 1984, pp. 2149-2154.
[16] S. F. Kendell, J. H. Krystal and G. Sanacora, “GABA and Glutamate Systems as Therapeutic Targets in Depression and Mood Disorders,” Expert Opinion on Therapeutic Targets, Vol. 9, No. 1, 2005, pp. 153-168.
[17] A. Guidotti, J. Auta, J. M. Davis, V. Di-Giorgi-Gerevini, Y. Dwivedi, D. R. Grayson, F. Impagnatiello, G. Pandey, C. Pesold, R. Sharma, D. Uzunov and E. Costa, “Decrease in Reelin and Glutamic Acid Decarboxylase67 (GAD67) Expression in Schizophrenia and Bipolar Disorder: A Postmortem Brain Study,” Archives of General Psychiatry, Vol. 57, No. 11, 2000, pp. 1061-1069.
[18] S. H. Fatemi, J. M. Stary, J. A. Earle, M. Araghi-Niknam and E. Eagan, “GABAergic Dysfunction in Schizophrenia and Mood Disorders as Reflected by Decreased Levels of Glutamic Acid Decarboxylase 65 and 67 kDa and Reelin Proteins in Cerebellum,” Schizophrenia Research, Vol. 72, No. 2-3, 2005, pp. 109-122.
[19] G. Bartholini, “Potential Therapeutic Activity of GABA-Mimetic Drugs in Neuropsychiatry,” Schweizer Archiv für Neurologie, Neurochirurgie and Psychiatrie, Vol. 125, No. 2, 1979, pp. 265-269.
[20] G. Magni, M. Garreau, B. Orofiamma and R. Palminteri, “Fengabine, a New GABAmimetic Agent in the Treatment of Depressive Disorders: An Overview of Six Double-Blind Studies versus Tricyclics,” Neuropsychobiology, Vol. 20, No. 3, 1989, pp. 126-131.
[21] N. P. Nielsen, B. Cesana, S. Zizolfi, V. Ascalone, P. Priore and P. L. Morselli, “Therapeutic Effects of Fengabine, a New GABAergic Agent, in Depressed Outpatients: A Doubleblind Study versus Clomipramine,” Acta Psychiatrica Scandinavica, Vol. 82, No. 5, 1990, pp. 366-371.
[22] L. L. Carpenter, J. M. Schecter, A. R. Tyrka, A. F. Mello, M. F. Mello, R. Haggarty and L. H. Price, “Open-Label Tiagabine Monotherapy for Major Depressive Disorder with Anxiety,” Journal of Clinical Psychiatry, Vol. 67, No. 1, 2006, pp. 66-71.
[23] K. G. Lloyd, P. L. Morselli and G. Bartholini, “GABA and Affective Disorders,” Medical Biology, Vol. 65, No. 2-3, 1987, pp. 159-165.
[24] K. G. Lloyd, B. Zivkovic, D. Sange, H. Depoortere and G. Bartholini, “Fengabine, a Novel Antidepressant GABAergic Agent. I. Activity in Models for Antidepressant Drugs and Psychopharmacological Profile,” Journal of Pharmacology and Experimental Therapeutics, Vol. 242, No. 1, 1987, pp. 245-250.
[25] J. Atsmon, S. Oaknin, M. Laudon, S. Laschiner, M. Gavish, Y. Dagan and N. Zisapel, “Reciprocal Effects of Chronic Diazepam and Melatonin on Brain Melatonin and Benzodiazepine Binding Sites,” Journal of Pineal Research, Vol. 20, No. 2, 1996, pp. 65-71.
[26] Y. Djeridane and Y. Touitou, “Chronic Diazepam Administration Differentially Affects Melatonin Synthesis in Rat Pineal and Harderian Glands,” Psychopharmacology, Vol. 154, No. 4, 2001, pp. 403-407.
[27] Y. Djeridane and Y. Touitou, “Effects of Diazepam and Its Metabolites on Nocturnal Melatonin Secretion in the Rat Pineal and Harderian Glands. A Comparative in Vivo and in Vitro Study,” Chronobiology International, Vol. 20, No. 2, 2003, pp. 285-297.
[28] F. Loiseau, C. Le Bihan, M. Hamon and M. H. Thiébot, “Effects of Melatonin and Agomelatine in Anxiety-Related Procedures in Rats: Interaction with Diazepam,” European Neuropsychopharmacology, Vol. 16, No. 6, 2006, pp. 417-428.
[29] I. V. Zhdanova and M. Giorgetti, “Melatonin Alters Behavior and cAMP Levels in Nucleus Accumbens Induced by Cocaine Treatment,” Brain Research, Vol. 956, No. 2, 2002, pp. 323-331.
[30] D. A. Golombek, M. Martini and D. P. Cardinali, “Melatonin as an Anxiolytic in Rats: Time Dependence and Interaction with the Central GABAergic System,” European Journal of Pharmacology, Vol. 237, No. 2-3, 1993, pp. 231-236.
[31] G. Pierrefiche, R. Zerbib and H. Laborit, “Anxiolytic Activity of Melatonin in Mice: Involvement of Benzodiazepine Receptors,” Research Communications in Chemical Pathology and Pharmacology, Vol. 82, No. 2, 1993, pp. 131-142.
[32] L. P. Niles, D. S. Pickering and M. A. Arciszewski, “Effects of Chronic Melatonin Administration on GABA and Diazepam Binding in Rat Brain,” Journal of Neural Transmission, Vol. 70, No. 1-2, 1987, pp. 117-124.
[33] L. P. Niles, O. M. Pulido and D. S. Pickering, “Age-Related Changes in GABA and Benzodiazepine Receptor Binding in Rat Brain Are Influenced by Sampling Time,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol. 12, No. 2-3, 1988, pp. 337-344.
[34] C. Gentsch, M. Lichtsteiner and H. Feer, “Open Field and Elevated Plus-Maze: A Behavioural Comparison between Spontaneously Hypertensive (SHR) and Wistar-Kyoto (WKY) Rats and the Effects of Chlordiazepoxide,” Behavioural Brain Research, Vol. 25, No. 2, 1987, pp. 101-107.
[35] V. Carola, F. D’Olimpio, E. Brunamonti, F. Mangia and P. Renzi, “Evaluation of the Elevated Plus-Maze and Open-Field Tests for the Assessment of Anxiety-Related Behaviour in Inbred Mice,” Behavioural Brain Research, Vol. 134, No. 1-2, 2002, p. 49.
[36] S. K. Kulkarni and A. C. Sharma, “Elevated Plus-Maze: A Novel Psychobehavioral Tool to Measure Anxiety in Rodents,” Methods and Findings in Experimental and Clinical Pharmacology, Vol. 13, No. 8, 1991, pp. 573-577.
[37] E. B. Naranjo-Rodriguez, A. O. Osornio, E. Hernandez-Avitia, V. Mendoza-Fernandez and A. Escobar, “Anxiolytic-Like Actions of Melatonin, 5-Metoxytryptophol, 5-Hydroxytryptophol and Benzodiazepines on a Conflict Procedure,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol. 24, No. 1, 2000, pp. 117-129.
[38] R. D. Porsolt, G. Anton, N. Blavet and M. Jalfre, “Behavioural Despair in Rats: A New Model Sensitive to Antidepressant Treatments,” European Journal of Pharmacology, Vol. 47, No. 4, 1978, pp. 379-391.
[39] N. Benabid and A. Ouichou, “Affective Responses of Early Life Photoperiod in Male Rats,” Neurosciences and Medicine, Vol. 2, No. 3, 2011, pp. 185-191.
[40] N. Benabid, A. Mesfioui and A. Ouichou, “Effects of Photoperiod Regimen on Emotional Behaviour in Two Tests for Anxiolytic Activity in Wistar Rat,” Brain Research Bulletin, Vol. 75, No. 1, 2008, pp. 53-59.
[41] P. T.-H. Wong and Y. P. Ong, “Acute Antidepressant-Like and Antianxiety-Like Effects of Tryptophan in Mice,” Pharmacology, Vol. 62, 2001, pp. 151-156.
[42] D. Sokolovic, B. Djordjevic, G. Kocic, P. Babovic, G. Ristic, Z. Stanojkovic, D. M. Sokolovic, A. Veljkovic, A. Jankovic and Z. Radovanovic, “The Effect of Melatonin on Body Mass and Behaviour of Rats during an Exposure to Microwave Radiation from Mobile Phone,” Bratislavské Lekárske Listy, Vol. 113, No. 5, 2012, pp. 265-269.
[43] L. Krsková, M. Vrabcová and M. Zeman, “Effect of Melatonin on Exploration and Anxiety in Normotensive and Hypertensive Rats with High Activity of Renin-Angiotensin System,” Neuroendocrinology Letters, Vol. 28, No. 3, 2007, pp. 295-301.
[44] C. Kopp, E. Vogel, M. C. Rettori, P. Delagrange and R. Misslin, “The Effects of Melatonin on the Behavioural Disturbances Induced by Chronic Mild Stress in C3H/He Mice,” Behavioural Pharmacology, Vol. 10, No. 1, 1999, pp. 73-83.
[45] A. Karakas, H. Coskun, A. Kaya, A. Kücük and B. Gündüz, “The Effects of the Intraamygdalar Melatonin Injections on the Anxiety Like Behavior and the Spatial Memory Performance in Male Wistar Rats,” Behavioural Brain Research, Vol. 222, No. 1, 2011, pp. 141-150.
[46] L. A. Brotto, A. M. Barr and B. B. Gorzalka, “Sex Differences in Forced-Swim and Open-Field Test Behaviours after Chronic Administration of Melatonin,” European Journal of Pharmacology, Vol. 402, No. 1-2, 2000, pp. 87-93.
[47] V. Micale, A. Arezzi, L. Rampello and F. Drago, “Melatonin Affects the Immobility Time of Rats in the Forced Swim Test: The Role of Serotonin Neurotransmission,” European Neuropsychopharmacology, Vol. 16, No. 7, 2006, pp. 538-545.
[48] B. C. Detanico, A. L. Piato, J. J. Freitas, F. L. Lhullier, M. P. Hidalgo, W. Caumo and E. Elisabetsky, “Antidepressant-Like Effects of Melatonin in the Mouse Chronic Mild Stress Model,” European Journal of Pharmacology, Vol. 607, No. 1-3, 2009, pp. 121-125.
[49] Y. Ergün, F. O. Orhan and M. F. Karaaslan, “Combination Therapy of Imipramine and Melatonin: Additive Antidepressant Effect in Mouse Forced Swimming Test,” European Journal of Pharmacology, Vol. 591, No. 1-3, 2008, pp. 159-163.
[50] A. V. Shaji and S. K. Kulkarni, “Central Nervous System Depressant Activities of Melatonin in Rats and Mice,” Indian Journal of Experimental Biology, Vol. 36, No. 3, 1998, pp. 257-263.
[51] V. Raghavendra, G. Kaur and S. K. Kulkarni, “Anti-Depressant Action of Melatonin in Chronic Forced Swimming-Induced Behavioral Despair in Mice, Role of Peripheral Benzodiazepine Receptor Modulation,” European Neuropsychopharmacology, Vol. 10, No. 6, 2000, pp. 473-481.
[52] R. L. Gannon, E. Lungwitz, N. Batista, I. Hester, C. Huntley, A. Peacock, P. Delagrange and M. J. Millan, “The Benzodiazepine Diazepam Demonstrates the Usefulness of Syrian Hamsters as a Model for Anxiety Testing: Evaluation of Other Classes of Anxiolytics in Comparison to Diazepam,” Behavioural Brain Research, Vol. 218, No. 1, 2011, pp. 8-14.
[53] E. B. Arushanian, E. V. Beier and A. S. Bulgakova, “Pineal Melatonin Exhibits More Pronounced Antistressor Properties than Anxiolytic Diazepam,” Eksperimental’ naia i Klinicheskaia Farmakologiia, Vol. 70, No. 6, 2007, pp. 9-12.
[54] F. M. Coloma and L. P. Niles, “Melatonin Enhancement of [3H]-Gamma-Aminobutyric Acid and [3H] Muscimol Binding in Rat Brain,” Biochemical Pharmacology, Vol. 37, No. 7, 1988, pp. 1271-1274.
[55] C. S. Pang, S. F. Tsang and J. C. Yang, “Effects of Melatonin, Morphine and Diazepam on Formalin-Induced Nociception in Mice,” Life Sciences, Vol. 68, No. 8, 2001, pp. 943-951.
[56] G. H. El-Sokkary, “Melatonin and Vitamin C Administration Ameliorate Diazepam-Induced Oxidative Stress and Cell Proliferation in the Liver of Rats,” Cell Proliferation, Vol. 41, No. 1, 2008, pp. 168-176.
[57] D. H. Overstreet, O. Pucilowski, M. C. Retton, P. Delagrange and B. Guardiola-Lemaitre, “Effects of Melatonin Receptor Ligands on Swim Test Immobility,” NeuroReport, Vol. 9, No. 2, 1998, pp. 429-453.
[58] M. Bourin, E. Mocaer and R. Porsolt, “Antidepressant-Like Activity of S 20098 (Agomelatine) in the Forced Swimming Test in Rodents: Involvement of Melatonin and Serotonin Receptors,” Journal of Psychiatry and Neuroscience, Vol. 29, No. 2, 2004, pp. 126-133.
[59] M. L. Dubocovich, E. Mogilnicka and P. M. Areso, “Antidepressant-Like Activity of the Melatonin Receptor Antagonist, Luzindole (N-0774), in the Mouse Behavioral Despair Test,” European Journal of Pharmacology, Vol. 182, No. 2, 1990, pp. 313-325.

comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.