Repeated Ascorbic Acid Administration Alleviates Motor Impairment, Anxiety-Related Behaviors, and Sociability Deficits in Fluoxetine-Treated Juvenile Male Rats

Authors

Ojo Foluso Olamide

Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilesa, Ilesa (Nigeria)

Hassan Luqman Adepoju

Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilesa, Ilesa (Nigeria)

Adewole Ayodeji Oluwasegun

Department of Surgery, Obafemi Awolowo University Teaching Hospital, Ile-Ife (Nigeria)

Edward Tolulope Adefola

Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilesa, Ilesa (Nigeria)

Folorunso Kolade Pelumi

Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilesa, Ilesa (Nigeria)

Afolabi Olayemi

Department of Human Nutrition and Dietetics, Faculty of Basic Medical Sciences, University of Ilesa, Ilesa (Nigeria)

Onaolapo Mary Tolulope

Department of Nursing Science, Faculty of Nursing Sciences, Saint Peters University, New Jersey (Nigeria)

Ogundiran Reuben Jesulayomi

Department of Anatomy, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso (Nigeria)

Article Information

DOI: 10.51244/IJRSI.2025.12110069

Subject Category: Medicine

Volume/Issue: 12/11 | Page No: 768-778

Publication Timeline

Submitted: 2025-11-20

Accepted: 2025-11-27

Published: 2025-12-09

Abstract

Background: The debilitating impact of fluoxetine usage has been established in both animal studies and clinical trials.
Objective: This study aimed to evaluate the ameliorative impacts of ascorbic acid against fluoxetine-induced behavioral despair and social deficits in juvenile rats.
Methods: Thirty-two Juvenile male Wistar rats (80-100 grams) were randomly assigned into four groups of eight animals per group (n=8). Group A served as a normal control and had only access to feed and water; groups B and D received Ascorbic acid orally at 10mg/kg. Additionally, groups C and D received fluoxetine at 10mg/kg orally by gavage. The substances were administered five days per week for eight weeks. After the last administration, rats underwent neurobehavioral tests [motor coordination using the catalepsy bar test, anxiety-related behaviors with the elevated plus maze model, and sociability test (three-chamber social interaction paradigm)]. The analysis was performed using one-way analysis of variance (ANOVA) in Windows (version 0.98), followed by a post-hoc test (Tukey HSD) for inter-group comparisons. Results were presented as mean ± standard error of mean (S.E.M). The intergroup significant difference was accepted as p < 0.05.
Results:The feed intake, relative change in body weight, time spent in the open arm, and with the social stimulus results show a statistically significant decrease (p< 0.05) in group C compared to group A. Compared to group C, a statistically significant increase (p < 0.05) was observed in group D. In contrast, the catalepsy score, time spent in the closed arm, and in the empty chamber results show a statistically significant increase (p < 0.05) in group C compared to the control group A. Compared to group C, a statistically significant decrease (p < 0.05) was seen in group D.
Conclusion:The debilitating effects of fluoxetine administration, as confirmed in this study, warrant more rigorous monitoring of its use; further research is needed to establish these effects in humans.

Keywords

Behavioral-despair, Ascorbic Acid, Sociability, Fluoxetine, anti-depressants

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References

1. Ajose, O., & Olofinjana, O. (2023). Fluoxetine in children and adolescents with major depressive disorder: A systematic meta-analysis of randomized controlled trials. Journal of Child and Adolescent Psychopharmacology, 33(1), 12-22. https://doi.org/10.1089/cap.2022.0017 [Google Scholar] [Crossref]

2. Beasley, C. M., Jr, Koke, S. C., Nilsson, M. E., & Gonzales, J. S. (2000). Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated meta-analysis. Clinical therapeutics, 22(11), 1319–1330. https://doi.org/10.1016/s0149-2918(00)83028-3 [Google Scholar] [Crossref]

3. Grieb, Z. A., Voisin, D. A., Terranova, J. I., Norvelle, A., Michopoulos, V., Huhman, K. L., & Albers, H. E. (2022). Acute administration of fluoxetine increases social avoidance and risk assessment behaviors in a sex- and social stress-dependent manner in Syrian hamsters (Mesocricetus auratus). Pharmacology, biochemistry, and behavior, 214, 173353. https://doi.org/10.1016/j.pbb.2022.173353 [Google Scholar] [Crossref]

4. Garlow, S. J., Kinkead, B., Thase, M. E., Judd, L. L., Rush, A. J., Yonkers, K. A., Kupfer, D. J., Frank, E., Schettler, P. J., & Rapaport, M. H. (2013). Fluoxetine increases suicide ideation less than placebo during treatment of adults with minor depressive disorder. Journal of psychiatric research, 47(9), 1199–1203. https://doi.org/10.1016/j.jpsychires.2013.05.025 [Google Scholar] [Crossref]

5. Flores-Ramirez, F. J., Themann, A., Sierra-Fonseca, J. A., Garcia-Carachure, I., Castillo, S. A., Rodriguez, M., Lira, O., Preciado-Piña, J., Warren, B. L., Robison, A. J., & Iñiguez, S. D. (2021). Adolescent fluoxetine treatment mediates a persistent anxiety-like outcome in female C57BL/6 mice that is ameliorated by fluoxetine re-exposure in adulthood. Scientific reports, 11(1), 7758. https://doi.org/10.1038/s41598-021-87378-6 [Google Scholar] [Crossref]

6. Brambilla, P., Cipriani, A., Hotopf, M., & Barbui, C. (2005). Side-effect profile of fluoxetine in comparison with other SSRIs, tricyclic and newer antidepressants: a meta-analysis of clinical trial data. Pharmacopsychiatry, 38(2), 69–77. https://doi.org/10.1055/s-2005-837806 [Google Scholar] [Crossref]

7. Plevin, D., & Galletly, C. (2020). The neuropsychiatric effects of vitamin C deficiency: a systematic review. BMC psychiatry, 20(1), 315. https://doi.org/10.1186/s12888-020-02730-w [Google Scholar] [Crossref]

8. Innocent Effiom Offiong, Adeshina John Ajibade, Foluso Olamide Ojo, Kehinde Busuyi David & Folorunso Kolade Pelumi. (2024). Effects of Vitamin C on Aluminum Chloride- Induced Neurotoxicity on the Hippocampal Cortex of Adult Wistar Male Rats. Asian Journal of Medicine and Health, 22(10), 80–101. https://doi.org/10.9734/ajmah/2024/v22i101106 [Google Scholar] [Crossref]

9. Travica, N., Ried, K., Sali, A., Scholey, A., Hudson, I., & Pipingas, A. (2017). Vitamin C Status and Cognitive Function: A Systematic Review. Nutrients, 9(9), 960. https://doi.org/10.3390/nu9090960 [Google Scholar] [Crossref]

10. Kumar, R. S., Narayanan, S. N., & Nayak, S. (2009). Ascorbic acid protects against restraint stress-induced memory deficits in Wistar rats. Clinics (Sao Paulo, Brazil), 64(12), 1211–1217. https://doi.org/10.1590/S1807-59322009001200012 [Google Scholar] [Crossref]

11. Matisz, C. E., Badenhorst, C. A., & Gruber, A. J. (2021). Chronic unpredictable stress shifts rat behavior from exploration to exploitation. Stress (Amsterdam, Netherlands), 24(5), 635–644. https://doi.org/10.1080/10253890.2021.1947235 [Google Scholar] [Crossref]

12. Matallah, A., Guezi, R., & Bairi, A. (2022). Repeated restraint stress induced neurobehavioral and sexual hormone disorders in male rats. AIMS neuroscience, 9(2), 264–276. [Google Scholar] [Crossref]

13. https://doi.org/10.3934/Neuroscience.2022014 [Google Scholar] [Crossref]

14. Salami, S. A., Oreagba, F. O., Salahdeen, H. M., Olatunji-Bello, I. I., & Murtala, B. A. (2023). Vitamin C supplementation modulates crude oil contaminated water induced gravid uterine impaired contractile mechanism and foetal outcomes in Wistar rats. Journal of complementary & integrative medicine, 20(3), 548–555. https://doi.org/10.1515/jcim-2023-0081 [Google Scholar] [Crossref]

15. Jayakumar, S., Raghunath, G., Ilango, S., Vijayakumar, J., & Vijayaraghavan, R. (2017). Effect of Fluoxetine on the Hippocampus of Wistar Albino Rats in Cold Restraint Stress Model. Journal of clinical and diagnostic research : JCDR, 11(6), AF01–AF06. [Google Scholar] [Crossref]

16. https://doi.org/10.7860/JCDR/2017/26958.9953 [Google Scholar] [Crossref]

17. García, J., López-Ibor, J., & Sánchez, S. (2013). How to weigh wild animals without causing stress. PLoS ONE, 8(2), e56302. https://doi.org/10.1371/journal.pone.0056302 [Google Scholar] [Crossref]

18. Ojo F.O., Hassan L.A., Olaniyi O.S., Adetoro E.K., Lawal R.T. and Lawal M.B. Zingiber Officinale supplemented diet reversed lead-induced oxidative stress and cerebral cortex injuries in adult female Wistar rats. J Exp Clin Anat 2025; 22(1):22-26. https://dx.doi.org/10.4314/jeca.v22i1.3 [Google Scholar] [Crossref]

19. Szabó, J., Renczés, E., Borbélyová, V., Ostatníková, D., & Celec, P. (2024). Assessing sociability using the Three-Chamber Social Interaction Test and the Reciprocal Interaction Test in a genetic mouse model of ASD. Behavioral and brain functions : BBF, 20(1), 24. https://doi.org/10.1186/s12993-024-00251-0. [Google Scholar] [Crossref]

20. Onaolapo, O. J., Olopade, J. O., & Onaolapo, A. Y. (2012). Effect of sertraline on 6-hydroxydopamine-induced catalepsy in hemiparkinsonian rats. Annals of Biological Research, 3(6), 3062-3066. [Google Scholar] [Crossref]

21. Luciani, K. R., Frie, J. A., & Khokhar, J. Y. (2020). An open source automated bar test for measuring catalepsy in rats. eNeuro, 7(3), ENEURO.0488 19.2020. https://doi.org/10.1523/ENEURO.0488-19.2020 [Google Scholar] [Crossref]

22. Onaderu TA, onaolapo OJ, onaolapo AY Post-conceptional melatonin administration mitigates changes in neurobehaviour and cerebral cortex histomorphology in prenatal sodium valproate-exposed rats. Acta Bioscientia 2024:1(1);38-45 https://doi.org/10.71181/actabioscientia [Google Scholar] [Crossref]

23. Tong, G., Zhang, C., Li, H., Gao, X., Velu, P., Safargar, M., Prabahar, K., Xie, H., & Wang, X. (2025). The impact of fluoxetine on obesity and diabetes-related biomarkers in overweight and obese individuals: a systematic review and meta-analysis of randomized controlled trials. BMC psychiatry, 25(1), 977. https://doi.org/10.1186/s12888-025-07441-8 [Google Scholar] [Crossref]

24. Liu, L., Zhang, X., Xue, J., Zhao, L., Tang, P., Tian, Y., Fan, H., Hao, M., Zhao, X., Geng, F., Mo, D., Xia, L., & Liu, H. (2025). Associations between appetite loss and clinical features as well as inflammatory cytokines in adolescents with major depressive disorder. Frontiers in psychiatry, 16, 1583060. https://doi.org/10.3389/fpsyt.2025.1583060 [Google Scholar] [Crossref]

25. Serralde-Zuñiga, A. E., González-Garay, A. G., Rodríguez-Carmona, Y., & Meléndez-Mier, G. (2022). Use of Fluoxetine to Reduce Weight in Adults with Overweight or Obesity: Abridged Republication of the Cochrane Systematic Review. Obesity facts, 15(4), 473–486. https://doi.org/10.1159/000524995 [Google Scholar] [Crossref]

26. Kobayashi, K., Haneda, E., Higuchi, M., Suhara, T., & Suzuki, H. (2012). Chronic fluoxetine selectively upregulates dopamine D₁-like receptors in the hippocampus. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 37(6), 1500–1508. https://doi.org/10.1038/npp.2011.335 [Google Scholar] [Crossref]

27. Weng, M., Xie, X., Liu, C., Lim, K. L., Zhang, C. W., & Li, L. (2018). The Sources of Reactive Oxygen Species and Its Possible Role in the Pathogenesis of Parkinson's Disease. Parkinson's disease, 2018, 9163040. https://doi.org/10.1155/2018/9163040 [Google Scholar] [Crossref]

28. Novío, S., Núñez, M. J., Amigo, G., & Freire-Garabal, M. (2011). Effects of fluoxetine on the oxidative status of peripheral blood leucocytes of restraint-stressed mice. Basic & clinical pharmacology & toxicology, 109(5), 365–371. https://doi.org/10.1111/j.1742-7843.2011.00736.x [Google Scholar] [Crossref]

29. Ganguly, R., Kumar, R., & Pandey, A. K. (2022). Baicalin provides protection against fluoxetine-induced hepatotoxicity by modulation of oxidative stress and inflammation. World journal of hepatology, 14(4), 729–743. https://doi.org/10.4254/wjh.v14.i4.729 [Google Scholar] [Crossref]

30. Zylinska, L., Lisek, M., Guo, F., & Boczek, T. (2023). Vitamin C Modes of Action in Calcium-Involved Signaling in the Brain. Antioxidants (Basel, Switzerland), 12(2), 231. [Google Scholar] [Crossref]

31. https://doi.org/10.3390/antiox12020231 [Google Scholar] [Crossref]

32. Harrison, F. E., & May, J. M. (2009). Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free radical biology & medicine, 46(6), 719–730. [Google Scholar] [Crossref]

33. https://doi.org/10.1016/j.freeradbiomed.2008.12.018 [Google Scholar] [Crossref]

34. Farhan, M., & Haleem, D. J. (2016). Anxiolytic profile of fluoxetine as monitored following repeated administration in animal rat model of chronic mild stress. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society, 24(5), 571–578. [Google Scholar] [Crossref]

35. https://doi.org/10.1016/j.jsps.2015.03.006 [Google Scholar] [Crossref]

36. Suzuki, Y., Yamaguchi, Y., & Okabe, S. (2023). An exploratory study of behavioral traits and the establishment of social relationships in laboratory rats. PLoS ONE, 18(12), e0295280. [Google Scholar] [Crossref]

37. https://doi.org/10.1371/journal.pone.0295280 [Google Scholar] [Crossref]

38. Grieb, Z. A., Voisin, D. A., Terranova, J. I., Norvelle, A., Michopoulos, V., Huhman, K. L., & Albers, H. E. (2022). Acute administration of fluoxetine increases social avoidance and risk assessment behaviors in a sex- and social stress-dependent manner in Syrian hamsters (Mesocricetus auratus). Pharmacology, biochemistry, and behavior, 214, 173353. https://doi.org/10.1016/j.pbb.2022.173353 [Google Scholar] [Crossref]

39. Simmons, W. K., Burrows, K., Avery, J. A., Kerr, K. L., Bodurka, J., Savage, C. R., & Drevets, W. C. (2016). Depression-Related Increases and Decreases in Appetite: Dissociable Patterns of Aberrant Activity in Reward and Interoceptive Neurocircuitry. The American journal of psychiatry, 173(4), 418–428. https://doi.org/10.1176/appi.ajp.2015.15020162 [Google Scholar] [Crossref]

40. Simmons, W. K., Burrows, K., Avery, J. A., Kerr, K. L., Taylor, A., Bodurka, J., Potter, W., Teague, T. K., & Drevets, W. C. (2020). Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Molecular psychiatry, 25(7), 1457–1468. https://doi.org/10.1038/s41380-018-0093-6 [Google Scholar] [Crossref]

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