Prenatal Paroxetine Exposure Alters Oxidative, Inflammatory, Neurobehavioural, and Cholinergic Markers in the Hippocampus of Male and Female Mice Offspring in a Depression Model

• Israel Ofejiro Efejene

  Department of Pharmacology, Faculty of Basic Medical Sciences, Southern Delta University, Ozoro, Delta State, Nigeria , DELSU Joint Canada-Israel Neuroscience and Biopsychiatry Laboratory, Department of Pharmacology, Faculty of Allied Health Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

  Author

• Benneth Ben-Azu

  DELSU Joint Canada-Israel Neuroscience and Biopsychiatry Laboratory, Department of Pharmacology, Faculty of Allied Health Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria.

  Author

• Anthony Taghogho Eduviere

  DELSU Joint Canada-Israel Neuroscience and Biopsychiatry Laboratory, Department of Pharmacology, Faculty of Allied Health Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria.

  Author

• Osuvwe Clement Orororo

  Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

  Author

• Mega Obukohwo Oyovwi

  Department of Human Physiology, Faculty of Basic Medical Sciences, Southern Delta University, Ozoro, Delta State, Nigeria

  Author

• Michael Eromosele Aisuodionoe

  Department of Human Physiology, Faculty of Basic Medical Sciences, Southern Delta University, Ozoro, Delta State, Nigeria

  Author

• Abdulwasiu Adeniyi Busari

  Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Lagos State, Nigeria

  Author

Background: Depression is a debilitating mental disorder that is impairs behavioural abilities due to its symptomatic expression but much more severe in gestational period due to its impact on maternal and child’s health. The study focused on the impacts of paroxetine and stress on offspring health exploring its neurobehavioural across age trajectories of infancy, adolescent and adulthood while various oxidative, inflammatory and neurochemical enzymes biomarkers were assayed for in the brain hippocampal region.

Materials and Methods: Eighty female Swiss mice (25-30g) were induced with prenatal depression using chronic unpredictable mild stress (CUMS) in pregnant Swiss dams at gestation days (GD) 13 to 19. Group 1 which served as control, consisted offspring of non-CUMS-treated dams, and received saline (2 mL/kg,p.o). Groups 2 and 3 include offspring of non-CUMS-treated dams and received paroxetine (2.5mg/kg and 5mg/kg, p.o) from GDs 13-19. Group 4 consist of offspring of CUMS-exposed dams and served as CUMS control. Groups 5 and 6 consist of offspring of CUMS-exposed dams, treated with paroxetine (2.5 and 5 mg/kg, p.o) from GD 13-19. Offspring (pups: males and females) were weaned at postnatal day (PND) 21-22 and randomly assigned into 6 groups (n=10) above.

Results: Key findings showed that paroxetine causes reduced brain weight especially in female than male with an increase correct alternation activities in infancy and adulthood than in adolescent. It also reduces oxidative activities when compared to control but only have little effect in balancing oxidant in severe reversal conditions, while also potentiating neurochemical enzyme activity in female than in male. Paroxetine showed a marked reduction of pro-inflammatory cytokines activities in male and female mice offspring.

Conclusion: Paroxetine shows clinical importance in the management of gestational depression but shows altering effects in neuronal weight and enzymes, oxidation and concentration in release of cytokines in the hippocampal brain region.

1. Israel Ofejiro Efejene, Department of Pharmacology, Faculty of Basic Medical Sciences, Southern Delta University, Ozoro, Delta State, Nigeria, DELSU Joint Canada-Israel Neuroscience and Biopsychiatry Laboratory, Department of Pharmacology, Faculty of Allied Health Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

   None

1. Aaronson ST, Sears P, Ruvuna F, Bunker M, Conway CR, Dougherty DD, Reimherr FW, Schwartz TL, Zajecka JM. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: Comparison of response, remission, and suicidality. Am J Psychiatry. 2017; 174: 640–648. DOI: https://doi.org/10.1176/appi.ajp.2017.16010034

2. Aleksandrova LR, Phillips AG, Wang YT. Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatry Neurosci. 2017; 42(4): 222–229. DOI: https://doi.org/10.1503/jpn.160175

3. Al-Qahtani SM, Bryzgalova G, Valladolid-Acebes I, Korach-André M, Dahlman-Wright K, Efendić S, Berggren PO, Portwood N. 17β- Estradiol suppresses visceral adipogenesis and activates brown adipose tissue-specific gene expression. Horm Mol Biol Clin Invest. 2017; 29: 13–26. DOI: https://doi.org/10.1515/hmbci-2016-0031

4. Alqurashi GK, Hindi EA, Zayed MA, Abd El-Aziz GS, Alturkistani HA, Ibrahim RF, Al-Thepyani MA, Bakhlgi R, Alzahrani NA, Ashraf GM, Alghamdi BS. The impact of chronic unpredictable mild stress-induced depression on spatial, recognition and reference memory tasks in mice: Behavioral and histological study. Behav Sci. 2022; 12(6): 166. DOI: https://doi.org/10.3390/bs12060166

5. Bah AJ, James PB, Bah N, Sesay AB, Sevalie S, Kanu JS. Prevalence of anxiety, depression and post-traumatic stress disorder among Ebola survivors in northern Sierra Leone: A cross-sectional study. BMC Public Health. 2020; 20(1): 1391. DOI: https://doi.org/10.1186/s12889-020-09507-6

6. Bear HA, Edbrooke-Childs J, Norton S, Krause KR, Wolpert M. Systematic review and meta-analysis: outcomes of routine specialist mental health care for young people with depression and/or anxiety. J Am Acad Child Adolesc Psychiatry. 2019; 59(7): 810–841. DOI: https://doi.org/10.1016/j.jaac.2019.12.002

7. Beijers L, Wardenaar KJ, Van Loo HM, Schoevers RA. Data-driven biological subtypes of depression: Systematic review of biological approaches to depression subtyping. Mol Psychiatry. 2019; 24: 888–900. DOI: https://doi.org/10.1038/s41380-019-0385-5

8. Bekhbat M, Neigh GN. Sex differences in the neuro-immune consequences of stress: Focus on depression and anxiety. Brain Behav Immun. 2018; 67: 1–12. DOI: https://doi.org/10.1016/j.bbi.2017.02.006

9. Ben-Azu B, Nwoke EE, Umukoro S, Aderibigbe AO, Ajayi AM, Iwalewa EO. Evaluation of the neuro behavioral properties of naringin in Swiss mice. Drug Res. 2018:465–74. DOI: https://doi.org/10.1055/a-0575-3730

10. Bérard A, Iessa N, Chaabane S, Muanda FT, Boukhris T, Zhao JP. The risk of major cardiac malformations associated with paroxetine use during the first trimester of pregnancy: A systematic review and meta-analysis. Br J ClinPharmacol. 2016; 81: 589–600. DOI: https://doi.org/10.1111/bcp.12849

11. Bérard 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: e013372. DOI: https://doi.org/10.1136/bmjopen-2016-013372

12. Bergman K, Sarkar P, Glover V, O’Connor TG. Maternal prenatal cortisol and infant cognitive development: Moderation by infant–mother attachment. Biol Psychiatry. 2010; 67:1026–1032. DOI: https://doi.org/10.1016/j.biopsych.2010.01.002

13. Bleibel L, Sokołowska P, Henrykowska G, Owczarek J, Wiktorowska-Owczarek A. Unveiling the anti-inflammatory effects of antidepressants: A systematic review of human studies over the last decade. Pharmaceuticals (Basel). 2025; 18(6): 867. DOI: https://doi.org/10.3390/ph18060867

14. Bock J, Murmu MS, Biala Y, Weinstock M, Braun K. Prenatal stress and neonatal handling induce sex-specific changes in dendritic complexity and dendritic spine density in hippocampal subregions of prepubertal rats. Neuroscience. 2011; 193: 34–43. DOI: https://doi.org/10.1016/j.neuroscience.2011.07.048

15. Bourke CH, Capello CF, Rogers SM, Yu ML, Boss-Williams KA, Weiss JM, Stowe ZN, Owens MJ. Prenatal exposure to escitalopram and/or stress in rats: A prenatal stress model of maternal depression and its treatment. Psychopharmacology (Berl). 2013; 228: 231–241. DOI: https://doi.org/10.1007/s00213-013-3030-z

16. Bowman R, Frankfurt M, Luine V. Sex differences in anxiety and depression: Insights from adult rodent models of chronic stress and neural plasticity. Front BehavNeurosci. 2025; 19: 1591973. DOI: https://doi.org/10.3389/fnbeh.2025.1591973

17. Capriles N, Watson S Jr, Akil H. Individual differences in the improvement of cocaine-induced place preference response by the 5-HT2C receptor antagonist SB242084 in rats. Psychopharmacology (Berl). 2012; 220: 731–740. DOI: https://doi.org/10.1007/s00213-011-2524-9

18. Carlini VP, Poretti MB, Rask-Andersen M, Chavan RA, Ponzio MF, Sawant RS, de Barioglio SR, Schiöth HB, de Cuneo MF. Differential effects of fluoxetine and venlafaxine on memory recognition: Possible mechanisms of action. Prog Neuropsychopharmacol Biol Psychiatry. 2012; 38(2): 159–167. DOI: https://doi.org/10.1016/j.pnpbp.2012.03.004

19. Carrard A, Cassé F, Carron C, Burlet-Godinot S, Toni N, Magistretti PJ, Martin JL. Role of adult hippocampal neurogenesis in the antidepressant actions of lactate. Mol Psychiatry. 2021; 26(11): 6723–6635. DOI: https://doi.org/10.1038/s41380-021-01122-0

20. Caspani G, Kennedy S, Foster JA, Swann J. Gut microbial metabolites in depression: Understanding the biochemical mechanisms. Microbial Cell. 2019; 6: 454–481. DOI: https://doi.org/10.15698/mic2019.10.693

21. Gill H, Gill B, El-Halabi S, Chen-Li D, Lipsitz O, Rosenblat JD, Van Rheenen TE, Rodrigues NB, Mansur RB, Majeed A, Lui LMW, Nasri F, Lee Y, Mcintyre RS. Antidepressant medications and weight change: A narrative review. Obesity (Silver Spring). 2020; 28(11): 2064–2072. DOI: https://doi.org/10.1002/oby.22969

22. Grigoriadis S, VonderPorten EH, Mamisashvili L, Roerecke M, Rehm J, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A, Ross LE. Antidepressant exposure during pregnancy and congenital malformations: Is there an association? A systematic review and meta-analysis of the best evidence. J Clin Psychiatry. 2013; 74: e293–308. DOI: https://doi.org/10.4088/JCP.12r07966

23. Haider S, Saleem S, Perveen T, Tabassum S, Batool Z, Sadir S, Liaquat L, Madiha S. Age-related learning and memory deficits in rats: Role of altered brain neurotransmitters, acetylcholinesterase activity and changes in antioxidant defence system. Age (Dordr). 2014; 36(3): 1291–1302. DOI: https://doi.org/10.1007/s11357-014-9653-0

24. Haddad PM, Pal BR, Clarke P, Wieck A, Sridhiran S. Neonatal symptoms following maternal paroxetine treatment: Serotonin toxicity or paroxetine discontinuation syndrome? J Psychopharmacol. 2005; 19: 554–557. DOI: https://doi.org/10.1177/0269881105056554

25. Hanswijk SI, Spoelder M, Shan L, Verheij MMM, Muilwijk OG, Li W, Liu C, Kolk SM, Homberg JR. Gestational factors throughout fetal neurodevelopment: The serotonin link. Int J Mol Sci. 2020; 21(16): 5850. DOI: https://doi.org/10.3390/ijms21165850

26. Harrington RA, Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I. Serotonin hypothesis of autism: Implications for selective serotonin reuptake inhibitor use during pregnancy. Autism Res. 2013; 6: 149–168. DOI: https://doi.org/10.1002/aur.1288

27. Harris A, Seckl J. Glucocorticoids, prenatal stress and the programming of disease. HormBehav. 2011; 59: 279–289. DOI: https://doi.org/10.1016/j.yhbeh.2010.06.007

28. Hassamal S. Chronic stress, neuroinflammation, and depression: An overview of pathophysiological mechanisms and emerging anti-inflammatories. Front Psychiatry. 2023; 14: 1130989. DOI: https://doi.org/10.3389/fpsyt.2023.1130989

29. Hobel C, Culhane J. Role of psychosocial and nutritional stress on poor pregnancy outcome. J Nutr. 2003; 133: 1 709S–717S. DOI: https://doi.org/10.1093/jn/133.5.1709S

30. Hoynes H, Whitmore D, Almond D. Long-Run impacts of childhood access to the safety net. Am Econ Rev. 2016; 106(4): 903–934. DOI: https://doi.org/10.1257/aer.20130375

31. Hu Y, Zhou J, Fang L, Liu H, Zhan Q, Luo D, Zhou C, Chen J, Li Q, Xie P. Hippocampal synaptic dysregulation of exo/ endocytosis-associated proteins induced in a chronic mild-stressed rat model. Neuroscience. 2013; 230: 1–12. DOI: https://doi.org/10.1016/j.neuroscience.2012.08.026

32. Huizink AC, Mulder EJ, Buitelaar JK. Prenatal stress and risk for psychopathology: Specific effects or induction of general susceptibility? Psychol Bull. 2004; 130: 115–142. DOI: https://doi.org/10.1037/0033-2909.130.1.115

33. Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model—Are we there yet? Behav Brain Res. 2018: 79–90. DOI: https://doi.org/10.1016/j.bbr.2017.12.025

34. Jetsonen E, Didio G, Winkel F, Llach Pou M, Boj C, Kuczynski-Noyau L, Võikar V, Guirado R, Taira T, Lauri SE, Castrén E, Umemori J. Activation of TrkB in parvalbumin interneurons is required for the promotion of reversal learning in spatial and fear memory by antidepressants. Neuropsychopharmacology. 2023; 48(7): 1021–30. DOI: https://doi.org/10.1038/s41386-023-01562-y

35. Jiang HY, Pan LY, Zhang X, Zhang Z, Zhou YY, Ruan B. Altered gut bacterial-fungal interkingdom networks in patients with current depressive episode. Brain Behav. 2020; 10: e01677. DOI: https://doi.org/10.1002/brb3.1677

36. Jimenez-Solem E, Andersen JT, Petersen M, Broedbaek K, Andersen NL, Torp-Pedersen C, Poulsen HE. Prevalence of antidepressant use during pregnancy in Denmark: A nationwide cohort study. PLoS One. 2013; 8: e80040. DOI: https://doi.org/10.1371/journal.pone.0063034

37. Jin Y, Yu L, Li Y. Paroxetine effect on nerve growth factor, human neurotrophin-4, and brain-derived neurotrophic factor levels in post-stroke depression. MolNeurobiol. 2024; 61(10): 7890–7897. DOI: https://doi.org/10.1007/s12035-024-04084-w

38. Jobin-Gervais K, Sheehy O, Bérard A. Can we rely on pharmacy claims databases to ascertain maternal use of medications during pregnancy? Pharmacoepidemiol Drug Saf. 2013; 22: 76–82.

39. Jetsonen E, Didio G, Winkel F, Llach Pou M, Boj C, Kuczynski-Noyau L, Võikar V, Guirado R, Taira T, Lauri SE, Castrén E, Umemori J. Hippocampal protein expression is differentially affected by chronic paroxetine treatment in adolescent and adult rats. Front Pharmacol. 2013; 4: 86.

40. Kiecolt-Glaser JK, Wilson SJ, Bailey ML. Marital distress, depression, and a leaky gut: Translocation of bacterial endotoxin as a pathway to inflammation. Psychoneuro endocrinology. 2018; 98: 52–60. DOI: https://doi.org/10.1016/j.psyneuen.2018.08.007

41. Kivimäki M, Bartolomucci A, Kawachi I. The multiple roles of life stress in metabolic disorders. Nat Rev Endocrinol. 2023; 19(1): 10–27. DOI: https://doi.org/10.1038/s41574-022-00746-8

42. Kronenberg C, Jacobs R, Zucchelli E. The impact of a wage increase on mental health: Evidence from the UK minimum wage. Health, Econometrics and Data Group Working Paper. 2015; 15/08. University of York.

43. Kronsten VT, Tranah TH, Pariante CM, Shawcross DL. Gut-derived systemic inflammation as a driver of depression in chronic liver disease. J Hepatol. 2022; 76: 665–680. DOI: https://doi.org/10.1016/j.jhep.2021.11.008

44. Kulkarni J, Storch A, Baraniuk A, Gilbert H, Gavrilidis E, Worsley R. Antipsychotic use in pregnancy. Expert OpinPharmacother. 2015; 16: 1335–1345. DOI: https://doi.org/10.1517/14656566.2015.1041501

45. Labbé SM, Caron A, Lanfray D, Monge-Rofarello B, Bartness TJ, Richard D. Hypothalamic control of brown adipose tissue thermogenesis. Front Syst Neurosci. 2015; 9: 150. DOI: https://doi.org/10.3389/fnsys.2015.00150

46. Lavy V, Schlosser A, Shany A. Out of Africa: Human capital consequences of in utero conditions. NBER Working Paper. 2016: 21894. DOI: https://doi.org/10.3386/w21894

47. Li F, Wang Y, Wang X, Zhao Y, Xie F, Qian LJ. Dynamic effects of chronic unpredictable mild stress on the hippocampal transcriptome in rats. Mol Med Rep. 2022; 25(4): 110. DOI: https://doi.org/10.3892/mmr.2022.12626

48. Li MX, Li Q, Sun XJ. Increased Homer1-mGluR5 mediates chronic stress-induced depressive-like behaviours. Prog Neuropsychopharmacol Biol Psychiatry. 2019; 95: 109682. DOI: https://doi.org/10.1016/j.pnpbp.2019.109682

49. Li T, Zheng LN, Han XH. Fenretinide attenuates lipopolysaccharide-induced blood–brain barrier and depressive-like behaviour in mice by targeting Nrf-2 signalling. Biomed Pharmacother. 2020; 125: 109680. DOI: https://doi.org/10.1016/j.biopha.2019.109680

50. Li Y, Hao Y, Fan F, Zhang B. The role of the microbiome in insomnia, circadian disturbance and depression. Front Psychiatry. 2018; 669. DOI: https://doi.org/10.3389/fpsyt.2018.00669

51. Perlman G, Tanti A, Mechawar N. Parvalbumin interneuron alterations in stress-related mood disorders: a systematic review. Neurobiol Stress. 2021; 15: 100380. DOI: https://doi.org/10.1016/j.ynstr.2021.100380

52. Peng ZW, Xue F, Wang HN, Zhang RG, Chen YC, Wang Y, Zhang LY, Fan J, Tan QR. Paroxetine up-regulates neurogenesis in hippocampus-derived neural stem cell from fetal rats. Mol Cell Biochem. 2013; 375: 105–113. DOI: https://doi.org/10.1007/s11010-012-1533-2

53. Polen KN, Rasmussen SA, Riehle-Colarusso T. Association between reported venlafaxine use in early pregnancy and birth defects. Birth Defects Res A ClinMolTeratol. 2013; 97: 28–35. DOI: https://doi.org/10.1002/bdra.23096

54. Poletti S, Mazza MG, Benedetti F. Inflammatory mediators in major depression and bipolar disorder. Transl Psychiatry. 2024; 14(1): 247. DOI: https://doi.org/10.1038/s41398-024-02921-z

55. Van den Hove DL, Blanco CE, Scheepens A, Desbonnet L, Myint AM, Leonard BE, Prickaerts J, Steinbusch HW. Prenatal maternal paroxetine treatment and neonatal mortality in the rat: a preliminary study. Neonatology. 2008; 93(1): 52-55. DOI: https://doi.org/10.1159/000106433