Citalopram and Physical exercise for the Prevention of Stress-Induced Dysfunction in Male Wistar Rats
Prevention of Stress-Induced Dysfunction using drug and exercise
-
Akram Molamohammadi
,
Marzieh Dehghan Shasaltaneh
,
Nasser Naghdi
,
Rasool Hemayattalab
,
Hassan Gharayagh Zandi
Abstract
Objectives: Learning is essential for nearly all aspects of human behavior and perception. Among the factors that can disrupt learning and memory, stress is particularly significant, as it interferes with cognitive functioning and overall well-being. The present study aimed to evaluate and compare the effects of citalopram, treadmill-based aerobic exercise, and swimming on learning and memory performance in male Wistar rats exposed to stress.
Methods: To assess these interventions, animals were subjected to immobility stress, moderate-intensity treadmill running, swimming exercise, or citalopram administration (10 mg/kg body weight for four weeks), as well as various combinations of these interventions under stressed and non-stressed conditions, but citalopram was assessed in the presence of stress. The Morris water maze test was used to assess cognitive performance, particularly by measuring the distance traveled to reach the hidden platform.
Results: The results revealed that stress negatively impacted learning and memory. However, both forms of exercise alleviated stress-induced cognitive impairments, with swimming showing especially beneficial effects in enhancing learning and memory among stressed rats.
Conclusion: Contrary to expectations, administration of citalopram did not prevent stress-induced cognitive dysfunction. However, the beneficial effects of both forms of exercise were evident during the acquisition phase. Notably, physical exercise—particularly swimming—may serve as a potential non-pharmacological substitute, as its cognitive effects under stress differed significantly from those of treadmill training in the presence of citalopram.
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5. Yap TL, Davis LS. Physical activity: the science of health promotion through tailored messages. Rehabil Nurs. 2008;33(2):55-62. https://doi.org/10.1002/j.2048-7940.2008.tb00204.x.
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7. Loprinzi PD, Frith E. Protective and therapeutic effects of exercise on stress-induced memory impairment. J Physiol Sci 2019;69(1):1-12. https://doi.org/0.1007/s12576-018-0638-0.
8. Saadati H, Babri S, Ahmadiasl N, Mashhadi M. Effects of exercise on memory consolidation and retrieval of passive avoidance learning in young male rats. Asian J Sports Med. 2010;1(3):137–42. https://doi.org/10.5812/asjsm.34858.
9. Loprinzi PD, Day S, Hendry R, Hoffman S, Love A, Marable S, et al. The effects of acute exercise on short-and long-term memory: Considerations for the timing of exercise and phases of memory. Eur J Psychol. 2021;17(1):85. https://doi.org/10.5964/ejop.2955
10. Enayat P, Norouzizadeh F, Bahrami M, Saberi S, Solhirad M, Karimi-Zandi L. SSRIs and Alzheimer’s Disease: A Complex Relationship. Curr Behav Neurosci Rep. 2025;12(1):16-20. https://doi.org/10.1007/s40473-025-00309-x.
11. Sawant N, Kshirsagar S, Reddy PH, Reddy AP. Protective effects of SSRI, Citalopram in mutant APP and mutant Tau expressed dorsal raphe neurons in Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis. 2024;1870(2):166942. https://doi.org/10.1016/j.bbadis.2023. .
12. Kim J, Diamond D. The stressed hippocampus, synaptic plasticity and lost memories. Synaptic Plasticity and Lost Memories. 2002;3:453–62. https://doi.org/10.1038/nrn849.
13. Kim S-H, Kim H-B, Jang M-H, Lim B-V, Kim Y-J, Kim Y-P, et al. Treadmill exercise increases cell proliferation without altering of apoptosis in dentate gyrus of Sprague-Dawley rats. Life Sci. 2002;71(11):1331-40. https://doi.org/10.016/S0024-3205(02)01849-0.
14. Egashira N, Matsumoto Y, Mishima K, Iwasaki K, Fujioka M, Matsushita M, et al. Low dose citalopram reverses memory impairment and electroconvulsive shock-induced immobilization. Pharmacol Biochem Behav. 2006;83(1):161-7. https://doi.org/10.1016/j.pbb.2006.01.006.
15. Conrad CD. A critical review of chronic stress effects on spatial learning and memory. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(5):742-55. https://doi.org/10.1016/j.pnpbp.2009.11.003.
16. Ma W-P, Cao J, Tian M, Cui M-H, Han H-L, Yang Y-X, Xu L. Exposure to chronic constant light impairs spatial memory and influences long-term depression in rats. Neurosci Res. 2007;59(2):224-30. https://doi.org/10.1016/j.neures.2007.06.1474.
17. Wright RL, Conrad CD. Enriched environment prevents chronic stress-induced spatial learning and memory deficits. Behav brain Res. 2008;187(1):41-7. https://doi.org/10.1016/j.bbr.2007.08.025.
18. Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose GM, Meaney MJ. Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. J Neurosci. 1995;15(1):61-9. https://doi.org/10.1523/JNEUROSCI.15-01-00061.
19. Sousa N, Lukoyanov N, Madeira M, Almeida O, Paula-Barbosa M. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience. 2000;97(2):253-66. https://doi.org/10.1016/S0306-4522(00)00050-6.
20. Gouirand AM, Matuszewich L. The effects of chronic unpredictable stress on male rats in the water maze. Physiol Behav. 2005;86(1):21-31. https://doi.org/10.1016/j.physbeh.2005.06.027.
21. Moosavi M, Naghdi N, Maghsoudi N, Asl SZ. Insulin protects against stress-induced impairments in water maze performance. Behav brain Res. 2007;176(2):230-6. https://doi.org/10.1016/j.bbr.2006.10.011.
22. McLaughlin KJ, Gomez JL, Baran SE, Conrad CD. The effects of chronic stress on hippocampal morphology and function: an evaluation of chronic restraint paradigms. Brain Res. 2007;1161:56-64. https://doi.org/10.1016/j.brainres.2007.05.042.
23. Saadati H, Babri S, Ahmadiasl N, Mashhadi M. Effects of exercise on memory retrieval in passive avoidance learning in young male Wistar rats. Qom Univ Med Sci J. 2009;3(1):41-8. .
24. Van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA. 1999;96(23):13427-31. https://doi.org/10.1073/pnas.96.23.
25. Anderson BJ, Rapp DN, Baek DH, McCloskey DP, Coburn-Litvak PS, Robinson JK. Exercise influences spatial learning in the radial arm maze. Physiol Behav. 2000;70(5):425-9. https://doi.org/10.1016/S0031-9384(00)00282-1.
26. Kuhne LA, Ksiezarczyk A-M, Braumann K-M, Reer R, Jacobs T, Röder B, Hötting K. Cardiovascular exercise, learning, memory, and cytokines: Results of a ten-week randomized controlled training study in young adults. Biol Psychol. 2023;176:108466-80. https://doi.org/10.1016/j.biopsycho.2022.
27. Yau S-Y, Lau BW-M, So K-F. Adult hippocampal neurogenesis: a possible way how physical exercise counteracts stress. Cell transplantation. 2011;20(1):99-111. https://doi.org/10.3727/096368910X532846.
28. Majlessi N, Naghdi N. Impaired spatial learning in the Morris water maze induced by serotonin reuptake inhibitors in rats. Behav Pharmacol. 2002;13(3):237-42. https://doi.org/10.1097/00008877-200205000-00007.
29. Khakpai F, Zarrindast MR. The effect of nicotine on antidepressant and anxiolytic responses induced by citalopram and citicoline in mice. Acta Neurobiol Exp. 2023;83(2):194-202. https://doi.org/10.55782/ane-2023-017.
30. Archer T, Ögren S-O, Johansson G, Ross SB. The effect of acute zimeldine and alaproclate administration on the acquisition of two-way active avoidance: comparison with other antidepressant agents, test of selectivity and sub-chronic studies. Psychopharmacol. 1984;84(2):188-95. https://doi.org/10.1007/BF00427444.
31. Zhang Q, Yang C, Liu T, Liu L, Li F, Cai Y, et al. Citalopram restores short-term memory deficit and non-cognitive behaviors in APP/PS1 mice while halting the advance of Alzheimer's disease-like pathology. Neuropharmacol. 2018;131:475-86. https://doi.org/10.1016/j.neuropharm.2017.12.021.
32. Kim B-S, Kim M-Y, Leem Y-H. Hippocampal neuronal death induced by kainic acid and restraint stress is suppressed by exercise. Neuroscience. 2011;194:291-301. https://doi.org/10.1016/j.neuroscience.2011.06.029.
33. Bermejo J-L, Valldecabres R, Villarrasa-Sapiña I, Monfort-Torres G, Marco-Ahulló A, Do Couto BR. Increased cortisol levels caused by acute resistance physical exercise impair memory and learning ability. PeerJ. 2022;10:e13000- e23. https://doi.org/10.7717/peerj.
34. Ang E, Wong P, Moochhala S, Ng Y. Neuroprotection associated with running: is it a result of increased endogenous neurotrophic factors? Neuroscience. 2003;118(2):335-45. https://doi.org/10.1016/S0306-4522(02)00989-2.
35. Serra FT, dos Santos Cardoso F, Petraconi N, Dos Santos JCC, Araujo BHS, Arida RM, da Silva SG. Resistance exercise improves learning and memory and modulates hippocampal metabolomic profile in aged rats. Neurosci Lett. 2022;766:136322- 1326331. https://doi.org/10.1016/j.neulet.2021.136322.
2. Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, Petre CO. Role of brain norepinephrine in the behavioral response to stress. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(8):1214-24. https://doi.org/10.016/j.pnpbp.2005.08.007.
3. Brown TI, Gagnon SA, Wagner AD. Stress Disrupts Human Hippocampal-PrefrontalFunction during Prospective Spatial Navigation andHinders Flexible Behavior. Curr Biol. 2020:1–13. https://doi.org/0.1016/j.cub.2020.03.006.
4. Shors TJ. Stressful experience and learning across the lifespan. Annu Rev Psychol. 2006;57:55-85. https://doi.org/10.1146/annurev.psych.57.102904.90205.
5. Yap TL, Davis LS. Physical activity: the science of health promotion through tailored messages. Rehabil Nurs. 2008;33(2):55-62. https://doi.org/10.1002/j.2048-7940.2008.tb00204.x.
6. Sinaei M, Nazem F, Alaei H, Talebi A. The role of aerobic exercise training patterns on learning function and memory performance: A review article. KAUMS J (FEYZ). 2019;23(5):563-77.
7. Loprinzi PD, Frith E. Protective and therapeutic effects of exercise on stress-induced memory impairment. J Physiol Sci 2019;69(1):1-12. https://doi.org/0.1007/s12576-018-0638-0.
8. Saadati H, Babri S, Ahmadiasl N, Mashhadi M. Effects of exercise on memory consolidation and retrieval of passive avoidance learning in young male rats. Asian J Sports Med. 2010;1(3):137–42. https://doi.org/10.5812/asjsm.34858.
9. Loprinzi PD, Day S, Hendry R, Hoffman S, Love A, Marable S, et al. The effects of acute exercise on short-and long-term memory: Considerations for the timing of exercise and phases of memory. Eur J Psychol. 2021;17(1):85. https://doi.org/10.5964/ejop.2955
10. Enayat P, Norouzizadeh F, Bahrami M, Saberi S, Solhirad M, Karimi-Zandi L. SSRIs and Alzheimer’s Disease: A Complex Relationship. Curr Behav Neurosci Rep. 2025;12(1):16-20. https://doi.org/10.1007/s40473-025-00309-x.
11. Sawant N, Kshirsagar S, Reddy PH, Reddy AP. Protective effects of SSRI, Citalopram in mutant APP and mutant Tau expressed dorsal raphe neurons in Alzheimer's disease. Biochim Biophys Acta Mol Basis Dis. 2024;1870(2):166942. https://doi.org/10.1016/j.bbadis.2023. .
12. Kim J, Diamond D. The stressed hippocampus, synaptic plasticity and lost memories. Synaptic Plasticity and Lost Memories. 2002;3:453–62. https://doi.org/10.1038/nrn849.
13. Kim S-H, Kim H-B, Jang M-H, Lim B-V, Kim Y-J, Kim Y-P, et al. Treadmill exercise increases cell proliferation without altering of apoptosis in dentate gyrus of Sprague-Dawley rats. Life Sci. 2002;71(11):1331-40. https://doi.org/10.016/S0024-3205(02)01849-0.
14. Egashira N, Matsumoto Y, Mishima K, Iwasaki K, Fujioka M, Matsushita M, et al. Low dose citalopram reverses memory impairment and electroconvulsive shock-induced immobilization. Pharmacol Biochem Behav. 2006;83(1):161-7. https://doi.org/10.1016/j.pbb.2006.01.006.
15. Conrad CD. A critical review of chronic stress effects on spatial learning and memory. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34(5):742-55. https://doi.org/10.1016/j.pnpbp.2009.11.003.
16. Ma W-P, Cao J, Tian M, Cui M-H, Han H-L, Yang Y-X, Xu L. Exposure to chronic constant light impairs spatial memory and influences long-term depression in rats. Neurosci Res. 2007;59(2):224-30. https://doi.org/10.1016/j.neures.2007.06.1474.
17. Wright RL, Conrad CD. Enriched environment prevents chronic stress-induced spatial learning and memory deficits. Behav brain Res. 2008;187(1):41-7. https://doi.org/10.1016/j.bbr.2007.08.025.
18. Bodnoff SR, Humphreys AG, Lehman JC, Diamond DM, Rose GM, Meaney MJ. Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity, and hippocampal neuropathology in young and mid-aged rats. J Neurosci. 1995;15(1):61-9. https://doi.org/10.1523/JNEUROSCI.15-01-00061.
19. Sousa N, Lukoyanov N, Madeira M, Almeida O, Paula-Barbosa M. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience. 2000;97(2):253-66. https://doi.org/10.1016/S0306-4522(00)00050-6.
20. Gouirand AM, Matuszewich L. The effects of chronic unpredictable stress on male rats in the water maze. Physiol Behav. 2005;86(1):21-31. https://doi.org/10.1016/j.physbeh.2005.06.027.
21. Moosavi M, Naghdi N, Maghsoudi N, Asl SZ. Insulin protects against stress-induced impairments in water maze performance. Behav brain Res. 2007;176(2):230-6. https://doi.org/10.1016/j.bbr.2006.10.011.
22. McLaughlin KJ, Gomez JL, Baran SE, Conrad CD. The effects of chronic stress on hippocampal morphology and function: an evaluation of chronic restraint paradigms. Brain Res. 2007;1161:56-64. https://doi.org/10.1016/j.brainres.2007.05.042.
23. Saadati H, Babri S, Ahmadiasl N, Mashhadi M. Effects of exercise on memory retrieval in passive avoidance learning in young male Wistar rats. Qom Univ Med Sci J. 2009;3(1):41-8. .
24. Van Praag H, Christie BR, Sejnowski TJ, Gage FH. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc Natl Acad Sci USA. 1999;96(23):13427-31. https://doi.org/10.1073/pnas.96.23.
25. Anderson BJ, Rapp DN, Baek DH, McCloskey DP, Coburn-Litvak PS, Robinson JK. Exercise influences spatial learning in the radial arm maze. Physiol Behav. 2000;70(5):425-9. https://doi.org/10.1016/S0031-9384(00)00282-1.
26. Kuhne LA, Ksiezarczyk A-M, Braumann K-M, Reer R, Jacobs T, Röder B, Hötting K. Cardiovascular exercise, learning, memory, and cytokines: Results of a ten-week randomized controlled training study in young adults. Biol Psychol. 2023;176:108466-80. https://doi.org/10.1016/j.biopsycho.2022.
27. Yau S-Y, Lau BW-M, So K-F. Adult hippocampal neurogenesis: a possible way how physical exercise counteracts stress. Cell transplantation. 2011;20(1):99-111. https://doi.org/10.3727/096368910X532846.
28. Majlessi N, Naghdi N. Impaired spatial learning in the Morris water maze induced by serotonin reuptake inhibitors in rats. Behav Pharmacol. 2002;13(3):237-42. https://doi.org/10.1097/00008877-200205000-00007.
29. Khakpai F, Zarrindast MR. The effect of nicotine on antidepressant and anxiolytic responses induced by citalopram and citicoline in mice. Acta Neurobiol Exp. 2023;83(2):194-202. https://doi.org/10.55782/ane-2023-017.
30. Archer T, Ögren S-O, Johansson G, Ross SB. The effect of acute zimeldine and alaproclate administration on the acquisition of two-way active avoidance: comparison with other antidepressant agents, test of selectivity and sub-chronic studies. Psychopharmacol. 1984;84(2):188-95. https://doi.org/10.1007/BF00427444.
31. Zhang Q, Yang C, Liu T, Liu L, Li F, Cai Y, et al. Citalopram restores short-term memory deficit and non-cognitive behaviors in APP/PS1 mice while halting the advance of Alzheimer's disease-like pathology. Neuropharmacol. 2018;131:475-86. https://doi.org/10.1016/j.neuropharm.2017.12.021.
32. Kim B-S, Kim M-Y, Leem Y-H. Hippocampal neuronal death induced by kainic acid and restraint stress is suppressed by exercise. Neuroscience. 2011;194:291-301. https://doi.org/10.1016/j.neuroscience.2011.06.029.
33. Bermejo J-L, Valldecabres R, Villarrasa-Sapiña I, Monfort-Torres G, Marco-Ahulló A, Do Couto BR. Increased cortisol levels caused by acute resistance physical exercise impair memory and learning ability. PeerJ. 2022;10:e13000- e23. https://doi.org/10.7717/peerj.
34. Ang E, Wong P, Moochhala S, Ng Y. Neuroprotection associated with running: is it a result of increased endogenous neurotrophic factors? Neuroscience. 2003;118(2):335-45. https://doi.org/10.1016/S0306-4522(02)00989-2.
35. Serra FT, dos Santos Cardoso F, Petraconi N, Dos Santos JCC, Araujo BHS, Arida RM, da Silva SG. Resistance exercise improves learning and memory and modulates hippocampal metabolomic profile in aged rats. Neurosci Lett. 2022;766:136322- 1326331. https://doi.org/10.1016/j.neulet.2021.136322.
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| Issue | Vol 3 No 3 (2025) | |
| Section | Original Articles | |
| Keywords | ||
| Citalopram Immobility stress Learning and Memory Swimming Treadmill | ||
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How to Cite
1.
Molamohammadi A, Dehghan Shasaltaneh M, Naghdi N, Hemayattalab R, Gharayagh Zandi H. Citalopram and Physical exercise for the Prevention of Stress-Induced Dysfunction in Male Wistar Rats. ABI. 2025;3(3):162-170.
