Effects of fluoxetine on memory under forced treadmill exercise conditions in male rats


1 Department of Biology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran

2 Department of Physiology, School of Medicine; Applied Physiology Research Center; Biosensor Research Center, Isfahan University of Medical Sciences, Isfahan, Iran


Background: Studies show inconsistent effects of forced exercise on cognitive processes. These differences are probably due to the stress of coercion in forced exercise. Because fluoxetine is used to treat complications caused by stress, this study aimed to evaluate the effects of fluoxetine on memory in rats under forced treadmill exercise.
Materials and Methods: Experimental groups were the control, the control exercise, the fluoxetine, and the fluoxetine exercise. The exercise program was treadmill running at 22 m/min, 0° inclination for 50 min/day, 6 days/week, for 4 weeks. Fluoxetine (5 mg/kg) was injected 30 min before treadmill. Morris water maze and passive avoidance learning tests were used for evaluation of memory. Acquisition phase of both tests were performed before interventions and memory was evaluated 1-day and 1-week after the last session of exercise and treatments.
Results: Our data showed that forced exercise impaired performance in passive avoidance learning test (P < 0.05 and P < 0.01, 1-day and 1-week after the last session of exercise and treatments, respectively). Spatial memory was only impaired after 1-week in the exercise group. Fluoxetine improved spatial memory after 1-day in the control group. However, it had no significant effects on memory in the exercise group.
Conclusion: The data correspond to the possibility that forced treadmill exercise can cause stress, and thereby cause damage to memory. The present results suggest that although fluoxetine may improve memory in intact rats but it cannot prevent damages that are caused by forced exercise.


Teri L, Gibbons LE, McCurry SM, Logsdon RG, Buchner DM, Barlow WE, et al. Exercise plus behavioral management in patients with Alzheimer disease: A randomized controlled trial. JAMA 2003;290:2015-22.  Back to cited text no. 1
Navarro A, Gomez C, López-Cepero JM, Boveris A. Beneficial effects of moderate exercise on mice aging: Survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol 2004;286:R505-11.  Back to cited text no. 2
Samorajski T, Delaney C, Durham L, Ordy JM, Johnson JA, Dunlap WP. Effect of exercise on longevity, body weight, locomotor performance, and passive-avoidance memory of C57BL/6J mice. Neurobiol Aging 1985;6:17-24.  Back to cited text no. 3
Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: Key roles of growth factor cascades and inflammation. Trends Neurosci 2007;30:464-72.  Back to cited text no. 4
Kim SH, Kim HB, Jang MH, Lim BV, Kim YJ, Kim YP, et al. Treadmill exercise increases cell proliferation without altering of apoptosis in dentate gyrus of Sprague-Dawley rats. Life Sci 2002;71:1331-40.  Back to cited text no. 5
Lee MH, Kim H, Kim SS, Lee TH, Lim BV, Chang HK, et al. Treadmill exercise suppresses ischemia-induced increment in apoptosis and cell proliferation in hippocampal dentate gyrus of gerbils. Life Sci 2003;73:2455-65.  Back to cited text no. 6
Sim YJ, Kim SS, Kim JY, Shin MS, Kim CJ. Treadmill exercise improves short-term memory by suppressing ischemia-induced apoptosis of neuronal cells in gerbils. Neurosci Lett 2004;372:256-61.  Back to cited text no. 7
Reisi P, Alaei H, Babri S, Sharifi MR, Mohaddes G. Effects of treadmill running on spatial learning and memory in streptozotocin-induced diabetic rats. Neurosci Lett 2009;455:79-83.  Back to cited text no. 8
Yosefi M, Reisi P, Alaei H, Pilehvarian AA, Rashidi B. Treadmill running improves spatial learning and memory in the rats with intracerebroventricular injection of streptozotocin. J Res Med Sci 2011;16:1386-7.  Back to cited text no. 9
[PUBMED]  Medknow Journal  
Asl NA, Sheikhzade F, Torchi M, Roshangar L, Khamnei S. Long-term regular exercise promotes memory and learning in young but not in older rats. Pathophysiology 2008;15:9-12.  Back to cited text no. 10
Jacobson MD, Raff MC. Programmed cell death and Bcl-2 protection in very low oxygen. Nature 1995;374:814-6.  Back to cited text no. 11
Jin Y, Lim CM, Kim SW, Park JY, Seo JS, Han PL, et al. Fluoxetine attenuates kainic acid-induced neuronal cell death in the mouse hippocampus. Brain Res 2009;1281:108-16.  Back to cited text no. 12
Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol Psychiatry 1999;46:1181-91.  Back to cited text no. 13
Xu H, Steven Richardson J, Li XM. Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus. Neuropsychopharmacology 2003;28:53-62.  Back to cited text no. 14
Watanabe Y, Gould E, Daniels DC, Cameron H, McEwen BS. Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 1992;222:157-62.  Back to cited text no. 15
Lim CM, Kim SW, Park JY, Kim C, Yoon SH, Lee JK. Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect. J Neurosci Res 2009;87:1037-45.  Back to cited text no. 16
Bianchi M, Sacerdote P, Panerai AE. Chlomipramine differently affects inflammatory edema and pain in the rat. Pharmacol Biochem Behav 1994;48:1037-40.  Back to cited text no. 17
Abdel-Salam OM, Baiuomy AR, Arbid MS. Studies on the anti-inflammatory effect of fluoxetine in the rat. Pharmacol Res 2004;49:119-31.  Back to cited text no. 18
Schiepers OJ, Wichers MC, Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:201-17.  Back to cited text no. 19
Gharzi M, Dolatabadi HR, Reisi P, Javanmard SH. Effects of different doses of doxepin on passive avoidance learning in rats. Adv Biomed Res 2013;2:66.  Back to cited text no. 20
[PUBMED]  Medknow Journal  
Manev R, Uz T, Manev H. Fluoxetine increases the content of neurotrophic protein S100beta in the rat hippocampus. Eur J Pharmacol 2001;420:R1-2.  Back to cited text no. 21
Hamidi G, Arabpour Z, Shabrang M, Rashidi B, Alaei H, Sharifi MR, et al. Erythropoietin improves spatial learning and memory in streptozotocin model of dementia. Pathophysiology 2013;20:153-8.  Back to cited text no. 22
Kramer AF, Hahn S, Cohen NJ, Banich MT, McAuley E, Harrison CR, et al. Ageing, fitness and neurocognitive function. Nature 1999;400:418-9.  Back to cited text no. 23
Van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci U S A 1999;96:13427-31.  Back to cited text no. 24
Sutoo D, Akiyama K. Regulation of brain function by exercise. Neurobiol Dis 2003;13:1-14.  Back to cited text no. 25
Barnes CA, Forster MJ, Fleshner M, Ahanotu EN, Laudenslager ML, Mazzeo RS, et al. Exercise does not modify spatial memory, brain autoimmunity, or antibody response in aged F-344 rats. Neurobiol Aging 1991;12:47-53.  Back to cited text no. 26
Ke Z, Yip SP, Li L, Zheng XX, Tong KY. The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: A rat brain ischemia model. PLoS One 2011;6:e16643.  Back to cited text no. 27
Kennard JA, Woodruff-Pak DS. A comparison of low- and high-impact forced exercise: Effects of training paradigm on learning and memory. Physiol Behav 2012;106:423-7.  Back to cited text no. 28
Arida RM, Scorza CA, da Silva AV, Scorza FA, Cavalheiro EA. Differential effects of spontaneous versus forced exercise in rats on the staining of parvalbumin-positive neurons in the hippocampal formation. Neurosci Lett 2004;364:135-8.  Back to cited text no. 29
Eichenbaum H, Otto T, Cohen NJ. The hippocampus - What does it do? Behav Neural Biol 1992;57:2-36.  Back to cited text no. 30
Lynch MA. Long-term potentiation and memory. Physiol Rev 2004;84:87-136.  Back to cited text no. 31
Sapolsky R. Stress, the Aging Brain and the Mechanisms of Neuron Death. Cambridge, MA: MIT Press; 1992.  Back to cited text no. 32
Tanapat P, Hastings NB, Rydel TA, Galea LA, Gould E. Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J Comp Neurol 2001;437:496-504.  Back to cited text no. 33
Gould E, Tanapat P, McEwen BS, Flügge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A 1998;95:3168-71.  Back to cited text no. 34
McEwen BS, de Leon MJ, Lupien SJ, Meaney MJ. Corticosteroids, the aging brain and cognition. Trends Endocrinol Metab 1999;10:92-96.  Back to cited text no. 35
McEwen BS, Sapolsky RM. Stress and cognitive function. Curr Opin Neurobiol 1995;5:205-16.  Back to cited text no. 36
Ang ET, Dawe GS, Wong PT, Moochhala S, Ng YK. Alterations in spatial learning and memory after forced exercise. Brain Res 2006;1113:186-93.  Back to cited text no. 37
Wyss JM, Chambless BD, Kadish I, van Groen T. Age-related decline in water maze learning and memory in rats: Strain differences. Neurobiol Aging 2000;21:671-81.  Back to cited text no. 38
Ampuero E, Stehberg J, Gonzalez D, Besser N, Ferrero M, Diaz-Veliz G, et al. Repetitive fluoxetine treatment affects long-term memories but not learning. Behav Brain Res 2013;247:92-100.  Back to cited text no. 39
Mercier G, Lennon AM, Renouf B, Dessouroux A, Ramaugé M, Courtin F, et al. MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes. J Mol Neurosci 2004;24:207-16.  Back to cited text no. 40
Lyons L, ElBeltagy M, Umka J, Markwick R, Startin C, Bennett G, et al. Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy. Psychopharmacology (Berl) 2011;215:105-15.  Back to cited text no. 41
Kim do H, Li H, Yoo KY, Lee BH, Hwang IK, Won MH. Effects of fluoxetine on ischemic cells and expressions in BDNF and some antioxidants in the gerbil hippocampal CA1 region induced by transient ischemia. Exp Neurol 2007;204:748-58.  Back to cited text no. 42
Dwivedi Y, Rizavi HS, Pandey GN. Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: Differential regulation of specific exons by antidepressants and corticosterone. Neuroscience 2006;139:1017-29.  Back to cited text no. 43
Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol 2010;70:289-97.  Back to cited text no. 44
Zarei G, Reisi P, Alaei H, Javanmard SH. Effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus of hippocampal formation in rats. Adv Biomed Res 2014;3:199.  Back to cited text no. 45
[PUBMED]  Medknow Journal