Effect of Prenatal Citalopram Exposure on Motor and Cognitive Functions of Rats

Ayşenur Zaimoğlu; Bahar Akyüz; S. Sırrı Bilge

doi:10.30565/medalanya.556757

Research Article

Effect of Prenatal Citalopram Exposure on Motor and Cognitive Functions of Rats

Year 2019, Volume: 3 Issue: 3, 213 - 219, 26.10.2019

Ayşenur Zaimoğlu Bahar Akyüz S. Sırrı Bilge

https://doi.org/10.30565/medalanya.556757

Abstract

Aim: Physicians mostly prescribe selective serotonin reuptake inhibitors in the treat-ment of depression in pregnancy. However, there is little information on teratogenic effects of selective serotonin reuptake inhibitors. This study aims to investigate the ef-fects of prenatal exposure to citalopram, one of the most prescribed antidepressants, on developmental characteristics, reflex and motor functions of rat pups.

Materials and Methods: 12-14 weeks old, pregnant Sprague-Dawley rats were used in the experiments. Rats were divided into 3 groups and separated into individual cag-es. When treatment groups received 5 and 20 mg/kg/d citalopram by orogastric ga-vage from gestational days 1 to 18, control group received the same amount of saline (2 ml/kg/d). After birth duration of gestation, number of live and dead pups and gross malformation are evaluated. Eye opening, pinna detachment, incisor eruption, the development of fur and weight gain were monitored as developmental parameters. Markers for reflex development were identified as righting reflex, negative geotaxis and grip response. Motor developments and cognitive functions were established with locomotor activity test, T-maze, holeboard, Y-maze and passive avoidance test.

Results: Developmental parameters, reflex, motor and cognitive development as-sessments of pups were not significantly different in treatment groups compared to control group.

Conclusion: The results of the study show that prenatal exposure to citalopram has no effect on motor and cognitive functions of rat offspring.

Keywords

Depression, selective serotonin re-uptake inhibitors, rat, citalopram, teratogenity

References

1. Kang HH, Ahn KH, Hong SC, Kwon BY, Lee EH, Lee JS, et al. Association of citalopram with congenital anomalies: A meta-analysis. Obstet Gynecol Sci. 2017;60(2):145-53. doi:10.5468/ogs.2017.60.2.145
2. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746-58. PMID: 19185342
3. Heikkinen T, Ekblad U, Laine K. Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta. Bjog-Int J Obstet Gy. 2002;109(9):1003-8. doi: 10.1111/j.1471-0528.2002.01467.x
4. Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use in pregnancy: a critical review focused on risks and controversies. Acta Psychiatr Scand. 2013;127(2):94-114. doi:10.1111/acps.12042
5. Sloot WN, Bowden HC, Yih TD. In vitro and in vivo reproduction toxicology of 12 monoaminergic reuptake inhibitors: possible mechanisms of infrequent cardiovascular anomalies. Reprod Toxicol. 2009;28(2):270-82. doi:10.1016/j.reprotox.2009.04.005
6. Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell A. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007; 356:2675-2683. doi: 10.1056/NEJMoa067407
7. Myles N, Newall H, Ward H, Large M. Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations. Aust N Z J Psychiatry. 2013;47(11):1002-12. doi:10.1177/0004867413492219
8. Berard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open. 2017;7(1):e013372. PMID: 28082367
9. de Castro VL, Destefani CR, Diniz C, Poli P. Evaluation of neurodevelopmental effects on rats exposed prenatally to sulfentrazone. Neurotoxicology. 2007;28(6):1249-59. doi:10.1016/j.neuro.2007.06.001
10. Motz BA, Alberts JR. The validity and utility of geotaxis in young rodents. Neurotoxicol Teratol. 2005;27(4):529-33. doi:10.1016/j.ntt.2005.06.005
11. Deacon RM, Rawlins JN. T-maze alternation in the rodent. Nat Protoc. 2006;1(1):7-12. doi:10.1038/nprot.2006.2
12. Moreira EG, Vassilieff I, Vassilieff VS. Developmental lead exposure: behavioral alterations in the short and long term. Neurotoxicol Teratol. 2001;23(5):489-95. doi: 10.1016/S0892-0362(01)00159-3
13. Gue M, Bravard A, Meunier J, Veyrier R, Gaillet S, Recasens M, et al. Sex differences in learning deficits induced by prenatal stress in juvenile rats. Behav Brain Res. 2004;150(1-2):149-57. doi:10.1016/S0166-4328(03)00250-X
14. Sadek B, Khan N, Darras FH, Pockes S, Decker M. The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats. Physiol Behav. 2016;165:383-91. doi:10.1016/j.physbeh.2016.08.022
15. Dubovicky M, Csaszarova E, Brnoliakova Z, Ujhazy E, Navarova J, Mach M. Effect of prenatal administration of venlafaxine on postnatal development of rat offspring. Interdiscip Toxicol. 2012;5(2):92-7. doi:10.2478/v10102-012-0016-3
16. Svirsky N, Levy S, Avitsur R. Prenatal exposure to selective serotonin reuptake inhibitors (SSRI) increases aggression and modulates maternal behavior in offspring mice. Dev Psychobiol. 2016;58(1):71-82. doi:10.1002/dev.21356
17. Santucci AK, Singer LT, Wisniewski SR, Luther JF, Eng HF, Dills JL, et al. Impact of prenatal exposure to serotonin reuptake inhibitors or maternal major depressive disorder on infant developmental outcomes. J Clin Psychiatry. 2014;75(10):1088-95. doi:10.4088/JCP.13m08902
18. Kobayashi T, Matsuyama T, Takeuchi M, Ito S. Autism spectrum disorder and prenatal exposure to selective serotonin reuptake inhibitors: A systematic review and meta-analysis. Reprod Toxicol. 2016;65:170-8. doi:10.1016/j.reprotox.2016.07.016
19. Klieger-Grossmann C, Weitzner B, Panchaud A, Pistelli A, Einarson T, Koren G, et al. Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study. J Clin Pharmacol. 2012;52(5):766-70. doi:10.1177/0091270011405524
20. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, National Birth Defects Prevention S. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356(26):2684-92. doi:10.1056/NEJMoa066584
21. Vasilakis-Scaramozza C, Aschengrau A, Cabral H, Jick SS. Antidepressant use during early pregnancy and the risk of congenital anomalies. Pharmacotherapy. 2013;33(7):693-700. doi:10.1002/phar.1211
22. Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569. doi:10.1136/bmj.b3569
23. Mulder EJ, Ververs FF, de Heus R, Visser GH. Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus. Neuropsychopharmacology. 2011;36(10):1961-71. doi:10.1038/npp.2011.67
24. Handal M, Skurtveit S, Furu K, Hernandez-Diaz S, Skovlund E, Nystad W, et al. Motor development in children prenatally exposed to selective serotonin reuptake inhibitors: a large population-based pregnancy cohort study. BJOG. 2016;123(12):1908-17. doi:10.1111/1471-0528.13582
25. Oberlander TF. Fetal serotonin signaling: setting pathways for early childhood development and behavior. J Adolesc Health. 2012;51(2 Suppl):S9-16. doi:10.1016/j.jadohealth.2012.04.009
26. Sprowles JL, Hufgard JR, Gutierrez A, Bailey RA, Jablonski SA, Williams MT, et al. Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats. Int J Dev Neurosci. 2016;54:39-52. doi:10.1016/j.ijdevneu.2016.08.007
27. Coleman FH, Christensen HD, Gonzalez CL, Rayburn WF. Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil). Am J Obstet Gynecol. 1999;181(5):1166-71. doi: 10.1016/S0002-9378(99)70102-X
28. Christensen HD, Rayburn WF, Gonzalez CL. Chronic prenatal exposure to paroxetine (Paxil) and cognitive development of mice offspring. Neurotoxicol Teratol. 2000;22(5):733-9. doi: 10.1016/S0892-0362(00)00099-4
29. Olivier JD, Valles A, van Heesch F, Afrasiab-Middelman A, Roelofs JJ, Jonkers M, et al. Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring. Psychopharmacology (Berl). 2011;217(3):419-32. PMID: 21487650

Prenatal Sitalopram Maruziyetinin Sıçanların Motor ve Kognitif Fonksiyonları Üzerine Etkisi

Year 2019, Volume: 3 Issue: 3, 213 - 219, 26.10.2019

Ayşenur Zaimoğlu Bahar Akyüz S. Sırrı Bilge

https://doi.org/10.30565/medalanya.556757

Abstract

Amaç: Seçici serotonin geri alım inhibitörleri gebelikte depresyon tedavisinde sıklıkla reçete edilmektedirler. Ancak bu gruptaki ilaçların teratojenik etkileriyle alakalı literatürde yeterli bilgi yoktur. Bu çalışmanın amacı; sık reçete edilen antidepresanlardan biri olan sitaloprama prenatal dönemdeki maruziyetin, sıçan yavrularının motor ve kognitif fonksiyonları üzerine etkilerinin araştırılmasıdır.

Materyal ve Metot: Deneylerde 12-14 haftalık gebe Sprague-Dawley sıçanlar kullanıldı. Sıçanlar üç gruba ayrıldı ve ayrı kafeslerde barındırıldılar. Tedavi gruplarına, 1 ila 18. günler arasında orogastrik gavaj ile 5 ve 20 mg/kg/gün sitalopram, kontrol grubuna ise aynı miktarda tuzlu su (2 ml/kg/gün) verildi. Doğumdan sonra gebelik süresi, canlı ve ölü yavru sayısı ve brüt malformasyon değerlendirildi. Gelişimsel parametre olarak göz açma, kulak kepçesinin ayrılması, kesici diş çıkması, tüylenme ve kilo alımı değerlendirildi. Righting refleks, negatif geotaksi ve grip response refleks gelişimini değerlendirmek için yapıldı. Motor gelişim ve kognitif fonksiyonların değerlendirilmesi için lokomotor aktivite testi, T-maze, holeboard, Y-maze, ve pasif sakınma testleri yapıldı.

Bulgular: Gelişimsel parametreler, refleks, motor ve kognitif gelişim açısından tedavi grubundaki sıçanlar ile kontrol grubundaki sıçanlar arasında anlamlı bir farklılık meydana gelmedi.

Sonuç: Bu çalışma ile sitaloprama maruziyetin yavrularda motor ve kognitif fonksiyonlar üzerinde değişikliğe sebep olmadığı gösterildi.

Keywords

Depresyon, seçici seratonin geri alım inhibitörleri, sıçan, sitalopram, teratojenite

References

1. Kang HH, Ahn KH, Hong SC, Kwon BY, Lee EH, Lee JS, et al. Association of citalopram with congenital anomalies: A meta-analysis. Obstet Gynecol Sci. 2017;60(2):145-53. doi:10.5468/ogs.2017.60.2.145
2. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373(9665):746-58. PMID: 19185342
3. Heikkinen T, Ekblad U, Laine K. Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta. Bjog-Int J Obstet Gy. 2002;109(9):1003-8. doi: 10.1111/j.1471-0528.2002.01467.x
4. Byatt N, Deligiannidis KM, Freeman MP. Antidepressant use in pregnancy: a critical review focused on risks and controversies. Acta Psychiatr Scand. 2013;127(2):94-114. doi:10.1111/acps.12042
5. Sloot WN, Bowden HC, Yih TD. In vitro and in vivo reproduction toxicology of 12 monoaminergic reuptake inhibitors: possible mechanisms of infrequent cardiovascular anomalies. Reprod Toxicol. 2009;28(2):270-82. doi:10.1016/j.reprotox.2009.04.005
6. Louik C, Lin AE, Werler MM, Hernandez-Diaz S, Mitchell A. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007; 356:2675-2683. doi: 10.1056/NEJMoa067407
7. Myles N, Newall H, Ward H, Large M. Systematic meta-analysis of individual selective serotonin reuptake inhibitor medications and congenital malformations. Aust N Z J Psychiatry. 2013;47(11):1002-12. doi:10.1177/0004867413492219
8. Berard A, Zhao JP, Sheehy O. Antidepressant use during pregnancy and the risk of major congenital malformations in a cohort of depressed pregnant women: an updated analysis of the Quebec Pregnancy Cohort. BMJ Open. 2017;7(1):e013372. PMID: 28082367
9. de Castro VL, Destefani CR, Diniz C, Poli P. Evaluation of neurodevelopmental effects on rats exposed prenatally to sulfentrazone. Neurotoxicology. 2007;28(6):1249-59. doi:10.1016/j.neuro.2007.06.001
10. Motz BA, Alberts JR. The validity and utility of geotaxis in young rodents. Neurotoxicol Teratol. 2005;27(4):529-33. doi:10.1016/j.ntt.2005.06.005
11. Deacon RM, Rawlins JN. T-maze alternation in the rodent. Nat Protoc. 2006;1(1):7-12. doi:10.1038/nprot.2006.2
12. Moreira EG, Vassilieff I, Vassilieff VS. Developmental lead exposure: behavioral alterations in the short and long term. Neurotoxicol Teratol. 2001;23(5):489-95. doi: 10.1016/S0892-0362(01)00159-3
13. Gue M, Bravard A, Meunier J, Veyrier R, Gaillet S, Recasens M, et al. Sex differences in learning deficits induced by prenatal stress in juvenile rats. Behav Brain Res. 2004;150(1-2):149-57. doi:10.1016/S0166-4328(03)00250-X
14. Sadek B, Khan N, Darras FH, Pockes S, Decker M. The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats. Physiol Behav. 2016;165:383-91. doi:10.1016/j.physbeh.2016.08.022
15. Dubovicky M, Csaszarova E, Brnoliakova Z, Ujhazy E, Navarova J, Mach M. Effect of prenatal administration of venlafaxine on postnatal development of rat offspring. Interdiscip Toxicol. 2012;5(2):92-7. doi:10.2478/v10102-012-0016-3
16. Svirsky N, Levy S, Avitsur R. Prenatal exposure to selective serotonin reuptake inhibitors (SSRI) increases aggression and modulates maternal behavior in offspring mice. Dev Psychobiol. 2016;58(1):71-82. doi:10.1002/dev.21356
17. Santucci AK, Singer LT, Wisniewski SR, Luther JF, Eng HF, Dills JL, et al. Impact of prenatal exposure to serotonin reuptake inhibitors or maternal major depressive disorder on infant developmental outcomes. J Clin Psychiatry. 2014;75(10):1088-95. doi:10.4088/JCP.13m08902
18. Kobayashi T, Matsuyama T, Takeuchi M, Ito S. Autism spectrum disorder and prenatal exposure to selective serotonin reuptake inhibitors: A systematic review and meta-analysis. Reprod Toxicol. 2016;65:170-8. doi:10.1016/j.reprotox.2016.07.016
19. Klieger-Grossmann C, Weitzner B, Panchaud A, Pistelli A, Einarson T, Koren G, et al. Pregnancy outcomes following use of escitalopram: a prospective comparative cohort study. J Clin Pharmacol. 2012;52(5):766-70. doi:10.1177/0091270011405524
20. Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM, National Birth Defects Prevention S. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007;356(26):2684-92. doi:10.1056/NEJMoa066584
21. Vasilakis-Scaramozza C, Aschengrau A, Cabral H, Jick SS. Antidepressant use during early pregnancy and the risk of congenital anomalies. Pharmacotherapy. 2013;33(7):693-700. doi:10.1002/phar.1211
22. Pedersen LH, Henriksen TB, Vestergaard M, Olsen J, Bech BH. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569. doi:10.1136/bmj.b3569
23. Mulder EJ, Ververs FF, de Heus R, Visser GH. Selective serotonin reuptake inhibitors affect neurobehavioral development in the human fetus. Neuropsychopharmacology. 2011;36(10):1961-71. doi:10.1038/npp.2011.67
24. Handal M, Skurtveit S, Furu K, Hernandez-Diaz S, Skovlund E, Nystad W, et al. Motor development in children prenatally exposed to selective serotonin reuptake inhibitors: a large population-based pregnancy cohort study. BJOG. 2016;123(12):1908-17. doi:10.1111/1471-0528.13582
25. Oberlander TF. Fetal serotonin signaling: setting pathways for early childhood development and behavior. J Adolesc Health. 2012;51(2 Suppl):S9-16. doi:10.1016/j.jadohealth.2012.04.009
26. Sprowles JL, Hufgard JR, Gutierrez A, Bailey RA, Jablonski SA, Williams MT, et al. Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats. Int J Dev Neurosci. 2016;54:39-52. doi:10.1016/j.ijdevneu.2016.08.007
27. Coleman FH, Christensen HD, Gonzalez CL, Rayburn WF. Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil). Am J Obstet Gynecol. 1999;181(5):1166-71. doi: 10.1016/S0002-9378(99)70102-X
28. Christensen HD, Rayburn WF, Gonzalez CL. Chronic prenatal exposure to paroxetine (Paxil) and cognitive development of mice offspring. Neurotoxicol Teratol. 2000;22(5):733-9. doi: 10.1016/S0892-0362(00)00099-4
29. Olivier JD, Valles A, van Heesch F, Afrasiab-Middelman A, Roelofs JJ, Jonkers M, et al. Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring. Psychopharmacology (Berl). 2011;217(3):419-32. PMID: 21487650

There are 29 citations in total.

Details

Primary Language	English
Subjects	Clinical Sciences
Journal Section	Research Article
Authors	Ayşenur Zaimoğlu This is me 0000-0001-6425-8439 Bahar Akyüz 0000-0001-5065-2136 S. Sırrı Bilge 0000-0003-2878-6968
Publication Date	October 26, 2019
Submission Date	April 22, 2019
Acceptance Date	June 19, 2019
Published in Issue	Year 2019 Volume: 3 Issue: 3

Cite

Vancouver	Zaimoğlu A, Akyüz B, Bilge SS. Effect of Prenatal Citalopram Exposure on Motor and Cognitive Functions of Rats. Acta Med. Alanya. 2019;3(3):213-9.

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