Administration of Zinc with Paroxetine Improved the Forced Swim Test Behavioral Pattern of Treated Mice in Acute and Sub-Acute Study


Despite progressive improvement in treating major depressive disorder (MDD), it remains mostly unresponsive to one antidepressant medication. Zinc is a brain highly abundant trace metal, a brain derived neurotrophic factor (BDNF) inducer, a modulator of synaptic plasticity and potent suppressor of the NMDA receptors. We proposed that co-administration of zinc with the antide-pressants may represent a valuable regimen to improve the efficacy of these drugs. This work has been implemented to evaluate the behavioral changes of acute and sub-acute co-administration of zinc with Paroxtine in mice. Methods: The animals were injected intra-peritoneal with either Paroxtine (20 mg/kg) which was a selective serotonin reuptake inhibitor (SSRI), zinc sulfate (30 mg/kg) or Paroxtine in combination with zinc for one day and one week (once daily). The pattern of the animal behavior was assessed in the forced swim test (FST). Results and Discussion: The behavioral patterns of the animals in the FST include immobility, swimming and climbing. Successful antidepressant should decrease the immobility time with either increase in swimming and/or climbing behavior based on the drug pharmacological activity. Our results revealed a significant decrease of immobility and increase of swimming behavior indicating serotonin-dependent pharmacological activity of Paroxtine or zinc alone as well as in the animals treated with zinc in combination with Paroxtine. There was no significant difference in the animals’ behavior between acute and sub-acute treatment with zinc or even upon its addition to paroxetine. Our data support the concept that co-administration of zinc may provide further antidepressant activity. Zinc may offer additional clinical value particularly in geriatric patients or other populations where zinc level has shown dramatic decrease.

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Refaey, H. , Amri, H. , Ashour, A. and Ahmed, A. (2015) Administration of Zinc with Paroxetine Improved the Forced Swim Test Behavioral Pattern of Treated Mice in Acute and Sub-Acute Study. Journal of Behavioral and Brain Science, 5, 213-220. doi: 10.4236/jbbs.2015.57022.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Yukihiko, S., Andrew, C.H., Shin, N., David, R.S. and Ronald, S.D. (2002) Brain-Derived Neurotrophic Factor Produces Antidepressant Effects in Behavioral Models of Depression. The Journal of Neuroscience, 8, 3251-3261.
[2] Schulz, R., Beach, S.R., Ives, D.G, Martire, L.M., Ariyo, A.A. and Kop, W.J. (2000) Association between Depression and Mortality in Older Adults: The Cardiovascular Health Study. Archives of Internal Medicine, 160, 1761-1768.
[3] Ciechanowski, P.S., Katon, W.J. and Russo, J.E. (2005) The Association of Depression and Perceptions of Interpersonal Relationships in Patients with Diabetes. Journal of Psychosomatic Research, 58, 139-144.
[4] Dechant, K.L. and Clissold, S.P. (1991) Paroxetine; a Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Depressive Illness. Drugs, 41, 225-253.
[5] Katzman, M.A. (2009) Current Considerations in the Treatment of Generalized Anxiety Disorder. CNS Drugs, 23, 103-120.
[6] Joffe, R.T., Levitt, A.J. and Sokolov, S.T. (1996) Augmentation Strategies. Journal of Clinical Psychiatry, 57, 25-31.
[7] United States Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research (1993) Depression in Primary Care. Vol. 2, Treatment of Major Depression. Government Printing Office, AHCPR Publication No. 93-0550, Rockville.
[8] Fava, M., Rappe, S.M., Pava, J.A., Nierenberg, A.A., Alpert, J.E. and Rosenbaum, J.F. (1995) Relapse in Patients on Long-Term Fluoxetine Treatment. Journal of Clinical Psychiatry, 56, 52-55.
[9] Ikmekcioglu, C. (2001) The Role of Trace Elements for the Health of Elderly Individuals. Die Nahrung, 45, 309-316.<309::AID-FOOD309>3.0.CO;2-0
[10] Prasad, A.S., Fitzgerald, J.T., Hess, J.W., Kaplan, J., Pelen, F. and Dardenn, M. (1993) Zinc Deficiency in Elderly Patients. Nutrition, 9, 218-224.
[11] Frederickson, C.J. (1989) Neurobiology of Zinc and Zinc-Containing Neurons. International Review of Neurobiology, 31, 145-238.
[12] Takeda, A. (2001) Zinc Homeostasis and Functions of Zinc in the Brain. Biometals, 14, 343-351.
[13] Takeda, A., Minami, A., Seki, Y. and Oku, N. (2003) Inhibitory Function of Zinc against Excitation of Hippocampal Glutamatergic Neurons. Epilepsy Research, 57, 169-174.
[14] Frederickson, C.J., Suh, S.W., Silva, D., Frederickson, C.J. and Thompson, R.B. (2000) Importance of Zinc in the Central Nervous System: The Zinc-Containing Neuron. The Journal of Nutrition, 130, 1471S-1483S.
[15] Nowak, G. and Szewczyk, B. (2002) Mechanisms Contributing to Anti-depressant Zinc Actions. Polish Journal of Pharmacology, 54, 587-592.
[16] Kroczka, B., Branski, P., Paucha, A., Pilc, A. and Nowak, G. (2001) Antidepressant-Like Properties of Zinc in Rodent Forced Swim Test. Brain Research Bulletin, 55, 297-300.
[17] Kroczka, B., Ziêba, A., Dudek, D., Pilc, A. and Nowak, G. (2000) Zinc Exhibits an Antidepressant-Like Effect in the Forced Swimming Test in Mice. Polish Journal of Pharmacology, 52, 403-406.
[18] Nowak, G., Legutkoa, B., Szewczyka, B., Pappa, M., Sanaka, M. and Pilc, A. (2004) Zinc Treatment Induces Cortical Brain-Derived Neurotrophic Factor Gene Expression. European Journal of Pharmacology, 492, 57-59.
[19] Nibuya, M., Morinobu, S. and Duman, R.S. (1995) Regulation of BDNF and trkB mRNA in Rat Brain by Chronic Electroconvulsive Seisure and Antidepressant Drug Treatments. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 15, 7539-7547.
[20] Nibuya, M., Nestler, E.J. and Duman, R.S. (1996) Chronic Antidepressant Administration Increases the Expression of cAMP Response Element Binding Protein (CREB) in Rat Hippocampus. Journal of Neuroscience, 16, 2365-2372.
[21] Malberg, J.E. and Blendy, J.A. (2005) Antidepressant Action: To the Nucleus and beyond. Trends in Pharmacological Sciences, 26, 631-638.
[22] Beyersmann, D. and Haase, H. (2001) Functions of Zinc in Signaling, Proliferation and Differentiation of Mammalian Cells. Biometals, 14, 331-341.
[23] Maes, M., De Vos, N., Demedts, P., Wauters, A. and Neels, H. (1999) Lower Serum Zinc in Major Depression in Relation to Changes in Serum Acute Phase Proteins. The Journal of Affective Disorders, 56, 189-194.
[24] Schlegel-Zawadzka, M., Ziêba, A., Dudek, D., Krooeniak, M., Szymaczek, M. and Nowak, G. (2000) Effect of Depression and of Antidepressant Therapy on Serum Zinc Levels—A Preliminary Clinical Study. In: Roussel, A.M., Favier, A.E. and Anderson, R.A., Eds., Trace Elements in Man and Animals 10, Kluwer Academic Plenum Press, Dordrecht, 607-610.
[25] Takeda, A. (2000) Movement of Zinc and Its Functional Significance in the Brain. Brain Research Reviews, 34, 137-148.
[26] Skolnick, P., Legutko, B., Li, X. and Bymaster, F.P. (2001) Current Perspectives on the Development of Non-Biogenic Amine-Based Antidepressants. Pharmacological Research, 43, 411-423.
[27] Szewczyk, B., Kata, R. and Nowak, G. (2001) Rise in Zinc Affinity for the NMDA Receptor Evoked by Chronic Imipramine is Species Specific. Polish Journal of Pharmacology, 53, 641-645.
[28] Nowak, G., Szewczyk, B., Wieronska, J.M., Branski, P., Palucha, A., Pilc, A., Sadlik, K. and Piekoszewski, W. (2003) Antidepressant-Like Effects of Acute and Chronic Treatment with Zinc in Forced Swim Test and Olfactory Bulbectomy Model in Rats. Brain Research Bulletin, 61, 159-164.
[29] Harmer, C.J., Goodwin, G.M. and Cowen, P.J. (2009) Why Do Antidepressants Take So Long to Work? A Cognitive Neuropsychological Model of Antidepressant Drug Action. The British Journal of Psychiatry, 195, 102-108.
[30] Porsolt, R.D., Le Pichon, M. and Jalfre, M. (1977) Depression: A New Animal Model Sensitive to Antidepressant Treatments. Nature, 266, 730-732.
[31] Detke, M.J., Rickels, M. and Lucki, I. (1995) Active Behaviors in the Rat Forced Swimming Test Differentially Produced by Serotonergic and Noradrenergic Antidepressants. Psychopharmacology, 121, 66-72.
[32] Stahl, S.M. (1997) Psychopharmacology of Antidepressants. Martin Duinz, London.
[33] Hollister, L.E. and Csernansky, J.G. (1990) Clinical Pharmacology of Psychotherapeutic Drugs. 3rd Edition, Churchill Livingstone, New York.
[34] Nowak, G. and Szewczyk, B. (2002) Mechanisms Contributing to Antidepressant Zinc Actions. Polish Journal of Pharmacology, 54, 587-592.
[35] Trullas, R. and Skolnick, P. (1990) Functional Antagonists at the NMDA Receptor Complex Exhibit Antidepressant Actions. European Journal of Pharmacology, 185, 1-10.
[36] Cunha, M.P., Machado, D.G., Bettino, L.E.B., Capra, J.C. and Rodrigues, A.L.S. (2008) Interaction of Zinc with Antidepressants in the Tail Suspension Test. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 32, 1913-1920.

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