Volume 26, Issue 1 (March 2022)                   Physiol Pharmacol 2022, 26(1): 39-48 | Back to browse issues page


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Abstract:   (1840 Views)
Introduction: Stress influences brain functions adversely but escitalopram exhibits positive effects on cognitive processes. Therefore, this study investigated the protective effects of different escitalopram doses on cognitive functions in rats under chronic stress and normal conditions. Methods: Forty-nine rats were randomly allocated into seven groups: control, sham, stress, escitalopram (10, 20 mg/kg/day) and stress-escitalopram (both doses). Initial latency, latency after 1-day, dark stay (DS) time and the number of entrances to the dark compartment were evaluated by passive avoidance test. Results: There were significant latency differences in stress and escitalopram10 groups compared to control group. Additionally, latencies showed significant enhancements in both 10 and 20 mg/kg/day stress-escitalopram groups compared to stress group and significant decrease in escitalopram20 group with respect to escitalopram10 group. DS time was significantly higher in stressed group and significantly lower in escitalopram10 groups, both compared to control group. Also, it was significantly lower in both stress-escitalopram groups in comparison with stress group. Furthermore, escitalopram20 group had a significantly higher DS time compared to escitalopram10 group. Finally, the number of entrances to the dark compartment was significantly lower in stress, escitalopram10 and stress-escitalopram10 groups compared to control group. Conclusion: Different doses of escitalopram affected brain functions under chronic stress and normal conditions. Escitalopram10 presented the most beneficial effects on improving brain functions under normal conditions. Whereas, both escitalopram doses showed similar protective effects on memory under stress. Overall, escitalopram at a dose of 10 mg/kg/day improved learning, memory consolidation and locomotor activity better than its maximum dose of 20 mg/kg/day.
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References
1. Aboukhatwa M, Dosanjh L, Luo Y. Antidepressants are a rational complementary therapy for the treatment of alzheimer's disease. Mol Neurodegener 2010; 5: 10. [DOI:10.1186/1750-1326-5-10]
2. Azorin JM, Llorca PM, Despiegel N, Verpillat P. Escitalopram is more effective than citalopram for the treatment of severe major depressive disorder. Encephale 2004; 30: 158-66. [DOI:10.1016/S0013-7006(04)95427-9]
3. Bahramzadeh Zoeram S, Elahdadi Salmani M, Lashkarbolouki T, Goudarzi I. Hippocampal orexin receptor blocking prevented the stress induced social learning and memory deficits. Neurobiol Learn Mem 2019; 157: 12-23. [DOI:10.1016/j.nlm.2018.11.009]
4. Benatti C, Alboni S, Blom JM, Gandolfi F, Mendlewicz J, Brunello N, et al. Behavioural and transcriptional effects of escitalopram in the chronic escape deficit model of depression. Behav Brain Res 2014; 272: 121-30. [DOI:10.1016/j.bbr.2014.06.040]
5. Bhagya V, Srikumar BN, Raju TR, Rao BS. Chronic escitalopram treatment restores spatial learning, monoamine levels, and hippocampal long-term potentiation in an animal model of depression. Psychopharmacology 2011; 214: 477-94. [DOI:10.1007/s00213-010-2054-x]
6. Bourke CH, Capello CF, Rogers SM, Megan LY, Boss-Williams KA, Weiss JM, et al. Prenatal exposure to escitalopram and/or stress in rats. Psychopharmacology 2013; 228: 231-41. [DOI:10.1007/s00213-013-3030-z]
7. Bui E, Orr SP, Jacoby RJ, Keshaviah A, LeBlanc NJ, Milad MR, et al. Two weeks of pretreatment with escitalopram facilitates extinction learning in healthy individuals. Hum psychopharmacology 2013; 28: 447-56. [DOI:10.1002/hup.2330]
8. Bundgaard C, Jørgensen M, Larsen F. Pharmacokinetic modelling of blood-brain barrier transport of escitalopram in rats. Biopharm Drug Dispos 2007; 28: 349-60. [DOI:10.1002/bdd.562]
9. Ceglia I, Acconcia S, Fracasso C, Colovic M, Caccia S, Invernizzi RW. Effects of chronic treatment with escitalopram or citalopram on extracellular 5-ht in the prefrontal cortex of rats: Role of 5-ht1a receptors. Br J Pharmacol 2004; 142: 469-78. [DOI:10.1038/sj.bjp.0705800]
10. Chang CH, Grace AA. Amygdala-ventral pallidum pathway decreases dopamine activity after chronic mild stress in rats. Biol Psychiatry 2014; 76: 223-30. [DOI:10.1016/j.biopsych.2013.09.020]
11. Diamond DM, Campbell AM, Park CR, Woodson JC, Conrad CD, Bachstetter AD, et al. Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 2006; 16: 571-6. [DOI:10.1002/hipo.20188]
12. Do Couto FS, Batalha VL, Valadas JS, Data-Franca J, Ribeiro JA, Lopes LV. Escitalopram improves memory deficits induced by maternal separation in the rat. Eur J Pharmacol 2012; 695: 71-5. [DOI:10.1016/j.ejphar.2012.08.020]
13. Do Nascimento EB, Dierschnabel AL, de Macêdo Medeiros A, Suchecki D, Silva RH, Ribeiro AM. Memory impairment induced by different types of prolonged stress is dependent on the phase of the estrous cycle in female rats. Horm Behav 2019; 115: 104563. [DOI:10.1016/j.yhbeh.2019.104563]
14. Drozd R, Rychlik M, Fijalkowska A, Rygula R. Effects of cognitive judgement bias and acute antidepressant treatment on sensitivity to feedback and cognitive flexibility in the rat version of the probabilistic reversal-learning test. Behav Brain Res 2019; 359: 619-29. [DOI:10.1016/j.bbr.2018.10.003]
15. Duque A, Vinader-Caerols C, Monleón S. Effects of social stress and clomipramine on emotional memory in mice. A Acta Neurobiol Exp (Wars) 2016; 76: 225-33. [DOI:10.21307/ane-2017-022]
16. Gammoh O, Mayyas F, Darwish Elhajji F. Chlorpheniramine and escitalopram: Similar antidepressant and nitric oxide lowering roles in a mouse model of anxiety. Biomed Rep 2017; 6: 675-80. [DOI:10.3892/br.2017.901]
17. Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, et al. Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 2011; 667: 222-9. [DOI:10.1016/j.ejphar.2011.05.012]
18. Hadad-Ophir O, Albrecht A, Stork O, Richter-Levin G. Amygdala activation and gabaergic gene expression in hippocampal sub-regions at the interplay of stress and spatial learning. Front Behav Neurosci 2014; 8: 3. [DOI:10.3389/fnbeh.2014.00003]
19. Ibrahim WW, Abdelkader NF, Ismail HM, Khattab MM. Escitalopram ameliorates cognitive impairment in d-galactose-injected ovariectomized rats: Modulation of jnk, gsk-3β, and erk signalling pathways. Sci Rep 2019; 9: 10056. [DOI:10.1038/s41598-019-46558-1]
20. Jastrzębska J, Frankowska M, Suder A, Wydra K, Nowak E, Filip M, et al. Effects of escitalopram and imipramine on cocaine reinforcement and drug-seeking behaviors in a rat model of depression. Brain Res 2017; 1673: 30-41. [DOI:10.1016/j.brainres.2017.07.016]
21. Jensen JB, du Jardin KG, Song D, Budac D, Smagin G, Sanchez C, et al. Vortioxetine, but not escitalopram or duloxetine, reverses memory impairment induced by central 5-ht depletion in rats: Evidence for direct 5-ht receptor modulation. Eur Neuropsychopharmacol 2014; 24: 148-59. [DOI:10.1016/j.euroneuro.2013.10.011]
22. Kalantarzadeh E, Radahmadi M, Reisi P. Effects of different dark chocolate diets on memory functions and brain corticosterone levels in rats under chronic stress. Physiol Pharmacol 2020; 24: 185-96. [DOI:10.32598/ppj.24.3.40]
23. Kaminska K, Rogoz Z. The antidepressant- and anxiolytic-like effects following co-treatment with escitalopram and risperidone in rats. J Physiol Pharmacol 2016; 67: 471-80.
24. Kirino E. Antidepressant efficacy of escitalopram in major depressive disorder; in: Melatonin, neuroprotective agents and antidepressant therapy. 2016; p. 465-76. [DOI:10.1007/978-81-322-2803-5_30]
25. Li XL, Yuan YG, Xu H, Wu D, Gong WG, Geng LY, et al. Changed synaptic plasticity in neural circuits of depressive-like and escitalopram-treated rats. Int J Neuropsychopharmacol 2015; 18. [DOI:10.1093/ijnp/pyv046]
26. Lim LW, Blokland A, Tan S, Vlamings R, Sesia T, Aziz-Mohammadi M, et al. Attenuation of fear-like response by escitalopram treatment after electrical stimulation of the midbrain dorsolateral periaqueductal gray. Exp Neurol 2010; 226: 293-300. [DOI:10.1016/j.expneurol.2010.08.035]
27. Lin CC, Tung CS, Liu YP. Escitalopram reversed the traumatic stress-induced depressed and anxiety-like symptoms but not the deficits of fear memory. Psychopharmacology 2016; 233: 1135-46. [DOI:10.1007/s00213-015-4194-5]
28. Ma L, Lu ZN, Hu P, Yao CJ. Neuroprotective effect of escitalopram oxalate in rats with chronic hypoperfusion. J Huazhong Univ Sci Technolog Med Sci 2015; 35: 514-18. [DOI:10.1007/s11596-015-1462-x]
29. McGaugh JL, Roozendaal B. Role of adrenal stress hormones in forming lasting memories in the brain. Curr Opin Neurobiol 2002; 12: 205-10. [DOI:10.1016/S0959-4388(02)00306-9]
30. Montezinho LP, Miller S, Plath N, Jensen NH, Karlsson J-J, Witten L, et al. The effects of acute treatment with escitalopram on the different stages of contextual fear conditioning are reversed by atomoxetine. Psychopharmacology 2010; 212: 131-43. [DOI:10.1007/s00213-010-1917-5]
31. Montgomery SA, Loft H, Sánchez C, Reines EH, Papp M. Escitalopram (s-enantiomer of citalopram): Clinical efficacy and onset of action predicted from a rat model. Pharmacol Toxicol 2001; 88: 282-6. [DOI:10.1034/j.1600-0773.2001.d01-118.x]
32. Mortazaei S, Sahraei H, Bahari Z, Meftahi GH, Pirzad Jahromi G, Hatef B. Ventral tegmental area inactivation alters hormonal, metabolic, and locomotor responses to inescapable stress. Arch Physiol Biochem 2019; 125: 293-301. [DOI:10.1080/13813455.2018.1455711]
33. Mowla A, Mosavinasab M, Haghshenas H, Borhani Haghighi A. Does serotonin augmentation have any effect on cognition and activities of daily living in alzheimer's dementia? A doubleblind, placebo-controlled clinical trial. J Clin Psychopharmacol 2007; 27: 484-7. [DOI:10.1097/jcp.0b013e31814b98c1]
34. Msetfi RM, Kumar P, Harmer CJ, Murphy RA. Ssri enhances sensitivity to background outcomes and modulates response rates: A randomized double blind study of instrumental action and depression. Neurobiol Learn Mem 2016; 131: 76-82. [DOI:10.1016/j.nlm.2016.03.004]
35. Murdoch D, Keam SJ. Escitalopram. Drugs 2005; 65: 2379-404. [DOI:10.2165/00003495-200565160-00013]
36. Patchev VK, Patchev AV. Experimental models of stress. Dialogues Clin Neurosci 2006; 8: 417-32. [DOI:10.31887/DCNS.2006.8.4/vpatchev]
37. Patki G, Solanki N, Atrooz F, Allam F, Salim S. Depression, anxiety-like behavior and memory impairment are associated with increased oxidative stress and inflammation in a rat model of social stress. Brain Res 2013; 1539: 73-86. [DOI:10.1016/j.brainres.2013.09.033]
38. Pechlivanova DM, Stoynev AG, Tchekalarova JD. The effects of chronic losartan pretreatment on restraint stress-induced changes in motor activity, nociception and pentylenetetrazol generalized seizures in rats. Folia Med (Plovdiv) 2011; 53: 69-73. [DOI:10.2478/v10153-010-0040-z]
39. Radahmadi M, Alaei H, Sharifi MR, Hosseini N. Effects of different timing of stress on corticosterone, BDNF and memory in male rats. Physiol Behav 2015; 139: 459-67. [DOI:10.1016/j.physbeh.2014.12.004]
40. Radahmadi M, Hosseini N, Alaei H, Sharifi MR. Effects of stress on serum and hippocampal il1β and glucose levels as well as retention in rats. Indian J Physiol Pharmacol 2017; 61: 141-51.
41. Ranjbar H, Radahmadi M, Alaei H, Reisi P, Karimi S. The effect of basolateral amygdala nucleus lesion on memory under acute,mid and chronic stress in male rats. Turk J Med Sci 2016; 46: 1915-25. [DOI:10.3906/sag-1507-7]
42. Ren QG, Wang YJ, Gong WG, Xu L, Zhang ZJ. Escitalopram ameliorates tau hyperphosphorylation and spatial memory deficits induced by protein kinase a activation in sprague dawley rats. J Alzheimers Dis 2015; 47: 61-71. [DOI:10.3233/JAD-143012]
43. Riga MS, Sanchez C, Celada P, Artigas F. Sub-chronic vortioxetine (but not escitalopram) normalizes brain rhythm alterations and memory deficits induced by serotonin depletion in rats. Neuropharmacology 2020; 178: 108238. [DOI:10.1016/j.neuropharm.2020.108238]
44. Rose EJ, Simonotto E, Spencer EP, Ebmeier KP. The effects of escitalopram on working memory and brain activity in healthy adults during performance of the n-back task. Psychopharmacology (Berl) 2006; 185: 339-47. [DOI:10.1007/s00213-006-0334-2]
45. Sánchez C, Gruca P, Bien E, Papp M. R-citalopram counteracts the effect of escitalopram in a rat conditioned fear stress model of anxiety. Pharmacol Biochem Behav. 2003; 75: 903-7. [DOI:10.1016/S0091-3057(03)00165-5]
46. Sardari M, Rezayof A, Zarrindast MR. 5-ht1a receptor blockade targeting the basolateral amygdala improved stress-induced impairment of memory consolidation and retrieval in rats. Neuroscience 2015; 300: 609-18. [DOI:10.1016/j.neuroscience.2015.05.031]
47. Schilström B, Konradsson-Geuken A, Ivanov V, Gertow J, Feltmann K, Marcus MM, et al. Effects of s-citalopram, citalopram, and r-citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, n-methyl-d-aspartate receptor-mediated transmission in the medial prefrontal cortex and cognitive function in the rat. Synapse (New York, NY) 2011; 65: 357-67. [DOI:10.1002/syn.20853]
48. Schöner J, Heinz A, Endres M, Gertz K, Kronenberg G. Post-traumatic stress disorder and beyond: An overview of rodent stress models. J Cell Mol Med 2017; 21: 2248-56. [DOI:10.1111/jcmm.13161]
49. Seo MK, Lee JG, Park SW. Effects of escitalopram and ibuprofen on a depression-like phenotype induced by chronic stress in rats. Neurosci Lett 2019; 696: 168-73. [DOI:10.1016/j.neulet.2018.12.033]
50. Shabani M, Divsalar K, Janahmadi M. Destructive effects of prenatal win 55212-2 exposure on central nervous system of neonatal rats. Addict Health 2012; 4: 9-19.
51. Shetty S, Hariharan A, Shirole T, Jagtap AG: Neuroprotective potential of escitalopram against behavioral, mitochondrial and oxidative dysfunction induced by 3-nitropropionic acid. Ann Neurosci neurosciences 2015; 22: 11-18. [DOI:10.5214/ans.0972.7531.220104]
52. Simoens VL, Istók E, Hyttinen S, Hirvonen A, Näätänen R, Tervaniemi M. Psychosocial stress attenuates general sound processing and duration change detection. Psychophysiology 2007; 44: 30-38. [DOI:10.1111/j.1469-8986.2006.00476.x]
53. Tao C, Yan W, Li Y, Lu X. Effect of antidepressants on spatial memory deficit induced by dizocilpine. Psychiatry Res 2016; 244: 266-72. [DOI:10.1016/j.psychres.2016.03.035]
54. Thai CA, Zhang Y, Howland JG. Effects of acute restraint stress on set-shifting and reversal learning in male rats. Cogn Affect Behav Neurosci. 2013; 13: 164-73. [DOI:10.3758/s13415-012-0124-8]
55. Tran TT, Srivareerat M, Alkadhi KA. Chronic psychosocial stress triggers cognitive impairment in a novel at-risk model of alzheimer's disease. Neurobiol Dis 2010; 37: 756-63. [DOI:10.1016/j.nbd.2009.12.016]
56. Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 2009; 10: 397-409. [DOI:10.1038/nrn2647]
57. Vohora D, Pal S, Pillai K. Effect of locomotor activity on the passive avoidance test for the evaluation of cognitive function. Indian J Pharmacol 2000; 32: 242-5.
58. Wang YJ, Ren QG, Gong WG, Wu D, Tang X, Li XL, et al. Escitalopram attenuates β-amyloidinduced tau hyperphosphorylation in primary hippocampal neurons through the 5-ht1a receptor mediated akt/gsk-3β pathway. Oncotarget 2016; 7: 13328-39. [DOI:10.18632/oncotarget.7798]
59. Waugh J, Goa KL. Escitalopram. A review of its use in the management of major depressive and anxiety disorders. CNS Drugs 2003; 17: 343-62. [DOI:10.2165/00023210-200317050-00004]
60. Wood GE, Young LT, Reagan LP, McEwen BS. Acute and chronic restraint stress alter the incidence of social conflict in male rats. Horm Behav. 2003; 43: 205-13. [DOI:10.1016/S0018-506X(02)00026-0]
61. Wu C, Gong WG, Wang YJ, Sun JJ, Zhou H, Zhang ZJ, et al. Escitalopram alleviates stressinduced alzheimer's disease-like tau pathologies and cognitive deficits by reducing hypothalamic-pituitary-adrenal axis reactivity and insulin/gsk-3β signal pathway activity. Neurobiol Aging 2018; 67: 137-47. [DOI:10.1016/j.neurobiolaging.2018.03.011]
62. Xi G, Hui J, Zhang Z, Liu S, Zhang X, Teng G, et al. Learning and memory alterations are associated with hippocampal n-acetylaspartate in a rat model of depression as measured by 1hmrs. PloS One 2011; 6: 28686. [DOI:10.1371/journal.pone.0028686]
63. Yang SN, Wang YH, Tung CS, Ko CY, Liu YP. Effects of escitalopram on a rat model of persistent stress-altered hedonic activities: Towards a new understanding of stress and depression. Chin J Physiol 2015; 58: 404-11. [DOI:10.4077/CJP.2015.BAD335]
64. Zoladz PR, Park CR, Halonen JD, Salim S, Alzoubi KH, Srivareerat M, et al. Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia. Hippocampus 2012; 22: 577-89. [DOI:10.1002/hipo.20922]

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