Pinealectomy and Exogenous Melatonin Regulate Anxiety-Like and Depressive-Like Behaviors in Male and Female Wistar Rats


The main objective of this work was to 1) study the influence of endogenous melatonin (Mel) abolishment via pinealectomy and 2) explore exogenous Mel effect on anxiety-like and depressive-like behavior in male and female rats. Rats were shamoperated (Sh) or pinealectomized (Px) and following subgroups were selected 1) Px/NaCl (0.9%) and Sh/NaCl (0.9%) : rats injected subcutaneously, once daily for 8 weeks, with saline solution NaCl (0.9%) as vehicle; 2) Px/Mel (4 mg/Kg) and Sh/Mel (4 mg/Kg): Rats similarly injected with 4 mg/Kg of Mel. All animals were housed under a photoperiod of (LD:16/8). After different treatments animals were tested in the open-field test (OFT), elevated plus maze test (EPM) to determine anxiety-like behavior, and forced swimming test (FST) to evaluate depressive-like level. Our results revealed that level of anxiety-like and depressive-like behavior are significantly higher in Px/NaCl (0.9%) when compared to Sh/NaCl (0.9%) group, suggesting that pinelectomy induced an anxiogenic and depressant effects. The Px effects would be due to the absence of endogenous Mel synthesis and release. Additionally, we clearly demonstrated that the level of anxiety-like and depressive-like behavior are higher in Px/Mel (4 mg/Kg) and Sh/Mel when compared respectively to Px/NaCl (4 mg/Kg) and Sh/NaCl groups suggesting an anxiolytic and antidepressant effects of exogenous Mel. Behavioral responses were sex dependent since the difference between females and males, especially, after melatonin administration, were statistically significant. These experiments provide evidence that pinealectomy and Mel regulated emotionally behavior in male and female rats.

Share and Cite:

E. Zahra, O. Siham, M. Abdelhalim, E. Aboubakr and O. Ali, "Pinealectomy and Exogenous Melatonin Regulate Anxiety-Like and Depressive-Like Behaviors in Male and Female Wistar Rats," Neuroscience and Medicine, Vol. 3 No. 4, 2012, pp. 394-403. doi: 10.4236/nm.2012.34049.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] R. Hardeland, “Melatonin in Unicellular Organisms, Fungi, Macroalgae and Angiosperms: Consequences of Its Metabolism, Mediation of Environmental Signals and the Search for Its Primary Roles,” Bulletin de la Société Fran?aise d’écophysiologie, Vol. 24, 1998, pp. 13-14.
[2] B. Vivien-Roels, “Présence, Synthèse et R?le Possible de la mElatonine Chez les Invertébrés,” Bulletin de la Société Fran?aise d’Ecophysiologie, Vol. 24, 1998, pp. 14-19.
[3] J. Arendt, “Melatonin, Circadian Rhythms and Sleep,” The New England Journal of Medicine, Vol. 343, 2000, pp. 1114-1116. doi:10.1056/NEJM200010123431510
[4] 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 Part A: Physiology, Vol. 74, No. 1, 1983, pp. 155-159. doi:10.1016/0300-9629(83)90727-2
[5] D. C. Klein and R. Y. Moore, “Pineal N-Acetyltransferase and Hydroxyindole-O-Methyltransferase: Control by the Suprachiasmatic Nucleus,” Brain Research, Vol. 174, No. 2, 1979, pp. 245-262. doi:10.1016/0006-8993(79)90848-5
[6] R. Y. Moore, J. C. Speh and J. P. Card, “The Retinohypothalamic Tract Originates from a Distinct Subset of Retinal Ganglion Cells,” Journal of Comparative Neurology, Vol. 352, No. 3, 1995, pp. 351-366. doi:10.1002/cne.903520304
[7] D. C. Klein, D. Sugden and J. L. Weller, “Postsynaptic Alpha-Adrenergic Receptors Potentiate the Beta-Adrenergic Stimulation of Pineal Serotonin N-Acetyltransferase,” Proceeding of the National Academy of Sciences of the USA, Vol. 80, No. 2, 1983, pp. 599-603. doi:10.1073/pnas.80.2.599
[8] B. Poeggeler, S. Saarela, R. J. Reiter, D. X. Tan, L. D. Chen and L. C. Manchester, “Melatonin, a Highly Potent Endogeneous Radical Scavenger and Electron Donor, New Aspects of the Antioxidant Chemistry of this Indole Accessed in Vitro,” Annals of the New York Academy of Sciences, Vol. 738, No. XI-XII, 1994, pp. 419-420.
[9] D. C. Klein, “The Mammalian Melatonin Rhythm Generating System,” In: L. Watterberg, Ed., Light and Biological Rhythms in Man, Pergamon Press, New York, 1993, pp. 55-70.
[10] J. Arendt, “Melatonin and the Mammalian Pineal Gland,” In: J. Arendt, Ed., Melatonin and the Pineal Gland: Influence on Mammalian Seasonal and Circadian Physiology, Reviews of Reproduction, Vol. 3, 1998, pp. 13-22.
[11] B. D. Goldman and J. M. Darrow, “The Pineal Gland and Mammalian Photoperiodism,” Neuroendocrinology, Vol. 37, 1983, pp. 386-396. doi:10.1159/000123579
[12] P. Pévet, “The Role of the Pineal Gland in the Photoperiodic Control of Reproduction in Different Hamster Species,” Reproduction Nutrition Development, Vol. 28, No. 2B, 1988, pp. 443-458. doi:10.1051/rnd:19880310
[13] J. Borjigin, X. Li and S. H. Snyder, “The Pineal Gland and Melatonin: Molecular and Pharmacologic Regulation,” Annual Review of Pharmacology, Vol. 39, 1999, pp. 53-65. doi:10.1146/annurev.pharmtox.39.1.53
[14] A. Brzezinski, “Melatonin in Humans,” The New England Journal of Medicine, Vol. 336, 1997, pp. 86-95.
[15] J. Vanecek, “Inhibitory Effect of Melatonin on GnRH Induced LH Release,” Reviews of Reproduction, Vol. 4, No. 2, 1999, pp. 67-72.
[16] D. A. Golombek, P. Pévet and D. P. Cardinalli, “Melatonin Effects on Behavior: Posssible Mediation by the Central GABAergic System,” Neuroscience & Biobehavioral Reviews, Vol. 20, No. 3, 1996, pp. 403-412. doi:10.1016/0149-7634(95)00052-6
[17] G. L. Kovács, I. Gajari, G. Telegdy and K. Lissak, “Effects of Melatonin and Pinealectomy on Avoidance and Exploratory Activity in the Rat,” Physiology & Behavior, Vol. 13, No. 3, 1974, pp. 349-355. doi:10.1016/0031-9384(74)90087-0
[18] A. Argyriou, H. Prast and A. Philippu, “Melatonin Facilitates Short-Term Memory,” European Journal of Pharmacology, Vol. 349, No. 2-3, 1998, pp. 159-162. doi:10.1016/S0014-2999(98)00300-8
[19] A. Karakas, H. Coskun, A. Kayaa, A. Kücükc and B. Gündüzd, “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. doi:10.1016/j.bbr.2011.03.029
[20] F. Loiseau, C. L. Bihan, M. Hamon and M. H. Thiebot, “Effects of Melatonin and Agomelatine in Anxiety-Related Procedures in Rats: Interaction with Diazepam,” European Neuropsychopharmacology, Vol. 16, No. 6, 2006, pp. 417-428. doi:10.1016/j.euroneuro.2005.11.007
[21] M. Mantovani, R. Pertile, J. B. Calixto, A. R. Santos and A. L. Rodrigues, “Melatonin Exerts an Antidepressant-Like Effect in the Tail Suspension Test in Mice: Evidence for Involvement of N-Methyl-D-Aspartate Receptors and the L-Arginine-Nitric Oxide Pathway,” Neuroscience Letters, Vol. 343, No. 1, 2003, pp. 1-4. doi:10.1016/S0304-3940(03)00306-9
[22] F. Z. El Mrabet, I. Lagbouri, A. Mesfioui, A. El hessni 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, p. 162.
[23] E. B. Naranjo-Rodriguez, A. Ortiz Orsornio, E. Hernandez-Avitia, V. Mendoza-Fernandez and A. Escobar, “Anxiolytic-Like Actions of Melatonin, 5-Methoxy-Tryptophan, 5-Hydroxytryptophol and Benzodiazepines on a Conflict Procedure,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol. 24, 2000, pp. 117-129.
[24] M. Papp, E. Litwa, P. Gruca and E. Mocaer, “Anxiolytic-Like Activity of Agomelatine and Melatonin in Three Animal Models of Anxiety,” Behavioural Pharmacology, Vol. 17, No. 1, 2006, pp. 9-18.
[25] J. Arendt. “Jet-Lag and Shift Work: (2). Therapeutic Use of Melatonin,” Journal of the Royal Society of Medicine, Vol. 92, No. 8, 1999, pp. 402-405.
[26] 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.
[27] M. Juszcak, J. Drobnik, J. W. Guzek and H. Schwarzberg, “Effect of Pinealectomy and Melatonin on Vasopressin-Potentiated Passive Avoidance in Rats,” Journal of Physiology and Pharmacology, Vol. 47, No. 4, 1996, pp. 621-627.
[28] J. L. Workman, Z. M. Weil, C. R. Tuthill and R. J. Nelson, “Maternal Pinealectomy Increases Depressive-Like Responses in Siberian Hamster Offspring,” Behavioural Brain Research, Vol. 189, No. 2, 2008, pp. 387-391. doi:10.1016/j.bbr.2008.01.016
[29] M. L. Dubocovich, P. Delagrange, D. N. Krause, D. Sugden, D. P. Cardinali and J. Olcese, “International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors,” Pharmacological Reviews, Vol. 62, No. 3, 2010, pp. 343-380. doi:10.1124/pr.110.002832
[30] M. L. Dubocovich, M. I. Masana and S. Benloucif, “Molecular Pharmacology and Function of Melatonin Receptor Subtypes,” In: J. Olcese, Ed., Melatonin after Four Decades: An Assessment of Its Potential, Vol. 20, New York, 2000, pp. 181-190.
[31] D. Mazurais, I. Brierley, I. Anglade, J. Drew, C. Randall, N. Bromage, D. Michel, O. Kah and L. M. Williams, “Central Melatonin Receptors in the Rainbow Trout: Comparative Distribution of Ligand Binding and Gene Expression,” Journal of Comparative Neurology, Vol. 409, No. 2, 1999, pp. 313-324. doi:10.1002/(SICI)1096-9861(19990628)409:2<313::AID-CNE11>3.0.CO;2-1
[32] M. Durand, O. Berton, S. Aguere, L. Edno, I. Combourieu, P. Mormède and F. Chaouloff, “Effects of Repeated Fluoxetine on Anxiety-Related Behaviour,” Journanl of Neuropharmacology, Vol. 38, No. 6, 1999, pp. 893-907.
[33] L. Schramm, M. P. McDonald and L. E. Limbird, “The Alpha(2A)-Adrenergic Receptor Plays a Protective Role in Mouse Behavioral Models of Depression and Anxiety,” The Journal of Neuroscience, Vol. 21, No. 13, 2001, pp. 4875-4882.
[34] L. Meyer, J. Caston and A. G. Mensah-Nyagan, “Seasonal Variation of the Impact of a Stressful Procedure on Open Field Behaviour and Blood Corticosterone in Laboratory Mice,” Behavioural Brain Research, Vol. 167, No. 2, 2006, pp. 342-348. doi:10.1016/j.bbr.2005.09.023
[35] F. Clénet, E. Bouyon, M. Hasco and M. Bourin, “Light/ Dark Cycle Manipulation Influences Mice Behavior in the Elevated Plus Maze,” Behavioural Brain Research, Vol. 166, No. 1, 2006, pp. 140-149. doi:10.1016/j.bbr.2005.07.018
[36] S. Pellower, P. Chopin, S. E. File and M. Briley, “Validation of Open: Closed Arms Entries in an Elevated Plus-Maze as a Measure of Anxiety in the Rat,” Journal of Neuroscience Methods, Vol. 14, No. 3, 1985, pp. 149-167. doi:10.1016/0165-0270(85)90031-7
[37] N. Benabid and A. Ouichou, “Affective Responses of Early Life Photoperiod in Male Wistar Rats,” Neurosciences and Medecine, Vol. 2, No. 3, 2011, pp. 185-191. doi:10.4236/nm.2011.23025
[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. doi:10.1016/0014-2999(78)90118-8
[39] 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. doi:10.1016/j.brainresbull.2007.07.016
[40] L. M. Pyter and R. J. Nelson, “Enduring Effects of Photoperiod on Affective Behaviors in Siberian Hamsters (Phodopus Sungorus),” Behavioral Neuroscience, Vol. 120, No. 1, 2006, pp. 125-134. doi:10.1037/0735-7044.120.1.125
[41] G. R. Dawson and M. D. Tricklebank, “Use of the Elevated Plus Maze in the Search for Novel Anxiolytic Agents,” Trends in Pharmacological Sciences, Vol. 16, No. 2, 1995, pp. 33-36. doi:10.1016/S0165-6147(00)88973-7
[42] L. Pickavance, M. Tadayyon, G. Williams and R. G. Vernon, “Lactation Suppresses Diurnal Rhythm of Serum Leptin,” Biochemical and Biophysical Research Communications, Vol. 248, No. 1, 1998, pp. 196-199. doi:10.1006/bbrc.1998.8934
[43] R. A. Hoffman and R. J. Reiter, “Rapid Pinealectomy in Hamsters and Other Small Rodents,” The Anatomical Record, Vol. 153, No. 1, 1965, pp. 19-21.
[44] A. Kaya, A. Karaka? and H. Co?kun, “The Effects of the Time of the Day and the Pinealectomy on Anxiety-Like Behaviour in Male Wistar Rats,” Biological Rhythm Research, Vol. 42, No. 5, 2011, pp. 367-383. doi:10.1080/09291016.2010.525380
[45] C. Kopp, E. Vogel, M. C. Rettori, P. Delagrange, P. Renard, D. Lesieur and R. Misslin, “Regulation of Emotional Behaviour by Day Length in Mice: Implication of Melatonin,” Behavioural Pharmacology, Vol. 10, No. 8, 1999, pp. 747-752.
[46] 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.
[47] 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. doi:10.1016/0014-2999(90)90290-M
[48] 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.
[49] F. P. Valle and B. B. Gorzalka, “Open-Field Sex Differences Prior to Puberty in Rats,” Bulletin of the Psychonomic Society, Vol. 16, No. 6, 1980, pp. 429-431.
[50] A. L. Brotto, M. A. 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. doi:10.1016/S0014-2999(00)00491-X
[51] M. S. Cohen, S. M. Kosslyn, H. C. Breiter, G. J. DiGirolamo, W. L. Thompson and A. K. Anderson, “Changes in Cortical Activity during Mental Rotation. A Mapping Study Using Functional MRI,” Brain, Vol. 119, No. 1, 1996, pp. 89-100. doi:10.1093/brain/119.1.89
[52] W. P. Pare and E. Redei, “Sex Differences and Stress Response to WKY Rats,” Physiology & Behavior, Vol. 54, No. 6, 1993, pp. 1179-1185. doi:10.1016/0031-9384(93)90345-G
[53] S. J. Alonso, M. A. Castellano, D. Afonso and M. Rodriguez, “Sex Differences in Behavioral Despair: Relationships between Behavioral Despair and Open Field Activity,” Physiology & Behavior, Vol. 49, No. 1, 1991, pp. 69-72. doi:10.1016/0031-9384(91)90232-D
[54] H. M. T. Barros and M. Ferigolo, “Ethopharmacology of Imipramine in the Forced-Swimming Test: Gender Differences,” Neuroscience & Biobehavioral Reviews, Vol. 23, No. 2, 1998, pp. 279-286. doi:10.1016/S0149-7634(98)00029-3
[55] C. M. Contreras, H. Lara-Morales, M. Molina-Hernandez, M. Saavedra and G. Arrellín-Rosas, “An Early Lesion of the Lateral Septal Nuclei Produces Changes in the Forced Swimming Test Depending on Gender,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, Vol. 19, No. 8, 1995, pp. 1277-1284. doi:10.1016/0278-5846(95)00266-9
[56] K. J. Ressler and C. B. Nemeroff, “Role of Serotoninergic and Noradrenergic Systems in the Pathophysiology of Depression and Anxiety Disorders,” Depression and Anxiety, Vol. 12, Suppl. 1, 2000, pp. 2-19. doi:10.1002/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4
[57] I. Kitayama, S. Nakamura and T. Yaga, “Degeneration of Locus Coeruleus Axons in Stress-Induced Depression Model,” Brain Research Bulletin, Vol. 35, No. 5-6, 1994, pp. 573-580. doi:10.1016/0361-9230(94)90171-6
[58] R. E. Rosenstein and D. P. Cardinali, “Melatonin Increases in Vivo Gaba Accumulation in Rat Hypothalamus, Cerebellum, Cerebral Cortex and Pineal Gland,” Brain Research, Vol. 398, No. 2, 1986, pp. 403-406.
[59] F. Xu, J. C. Li, K. C. Ma and M. Wang, “Effects of Melatonin on Hypothalamic Gamma-Aminobutyric Acid, Aspartic Acid, Glutamic Acid, Beta-Endorphin and Serotonin Levels in Male Mice,” Biological Signals, Vol. 4, No. 4, 1995, pp. 225-231.
[60] D. A. Golombek, P. Pevet and D. P. Cardinali, “Melatonin Effects on Behavior: Possible Mediation by the Central GABAergic System,” Neuroscience & Biobehavioral Reviews, Vol. 20, No. 3, 1996, pp. 403-412.

Copyright © 2024 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.