INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

RepeatedAscorbicAcidAdministrationAlleviates Motor Impairment,

Anxiety-Related Behaviors, and Sociability Deficits in Fluoxetine-Treated

Juvenile Male Rats

Ojo Foluso Olamide¹, Hassan Luqman Adepoju^1*, Adewole Ayodeji Oluwasegun², Edward Tolulope

Adefola¹, Folorunso Kolade Pelumi¹, Afolabi Olayemi³, Onaolapo Mary Tolulope⁴, Ogundiran Reuben

Jesulayomi⁵

¹Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilesa, Ilesa, Nigeria.

²Department of Surgery, Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria.

³Department of Human Nutrition and Dietetics, Faculty of Basic Medical Sciences, University of Ilesa,

Ilesa, Nigeria.

⁴Department of Nursing Science, Faculty of Nursing Sciences, Saint Peters University, New Jersey,

United States of America.

⁵Department of Anatomy, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology,

Ogbomoso, Nigeria.

⁶Department of Biochemistry, Faculty of Sciences, University of Ilesa, Ilesa, Nigeria.

*Corresponding Author

DOI: https://doi.org/10.51244/IJRSI.2025.12110069

Received: 20 November 2025; Accepted: 27 November 2025; Published: 09 December 2025

ABSTRACTS

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

Page 768

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

INTRODUCTION

Fluoxetine, a well-known selective serotonin reuptake inhibitor (SSRI) commonly used in the management of

depressive disorder, has received wide acceptance in clinical trials (1). The expected outcome has been

observed through its ability to modulate mood by regulating neurotransmitters such as serotonin and

dopamine, which are responsible for mood regulation.

However, in the last few decades, preclinical and clinical trials have established an association between

fluoxetine usage and some adverse effects, such as sexual dysfunction, tremor, anxiety, sociability disparity,

loss of appetite, and weight loss (2,3), among others. These adverse effects have often called for a careful

watch on patients undergoing treatment using fluoxetine. In fact, the onset of fluoxetine usage has been proven

to have a strong association with suicidal ideation (4). While its sexual dysfunctional effects have attracted

more attention, little or no attention has been considered worthy concerning its other adverse effects. Probably

because of their minimal deleterious impact on the population using it. Interestingly, recent studies have

established an increased prevalence of social interaction deficit and anxiety, particularly among young male

adults undergoing fluoxetine treatment (5). Moreover, Tremor, loss of appetite, and weight loss are also

established as associated adverse effects with its usage (6). It is therefore important not to overlook its adverse

effects that are considered minimal, but rather search for other possible supplements that will not impede its

efficacy in the treatment of depressive disorder, but will mitigate its adverse effects on the stated conditions.

Ascorbic acid, commonly known as vitamin C, is a water-soluble vitamin that plays an essential role in brain

health and function due to its antioxidant properties (7). Studies have established its significant reversal effects

on some behavioral deficits in rodents (8). Travica et al. (2017) in their study also reported its beneficial effects

on brain health (9), the ameliorative effects of ascorbic acid on memory and attention deficit, anxiety,

depressive behaviors, motor and social change (10,11, 12). Its ability to scavenge reactive oxygen species and

mitigate oxidative stress, as well as its effects on the hypothalamic-pituitary-adrenal (HPA) axis modulation, is

the commonly reported mechanism of action in the expression of these effects. Despite the reported beneficial

impact of ascorbic acid on brain health and behaviors, there is a paucity of scientific information regarding its

effects on the debilitating impact of fluoxetine usage in this shady area. The current study aims to evaluate its

mitigating impacts on the adverse depilating effects of fluoxetine usage.

MATERIALS AND METHODS

Drugs

Fluoxetine (Bristol Laboratories Ltd., Berkhamsted, Herts, HP4 1EG, UK), Ascorbic acid (100 mg, BIORAJ

Pharmaceuticals LTD, Nigeria), Distilled water, Elevated Plus Maze, Three chambers social interaction

paradigm, and Catalepsy rods.

Animals

Healthy Juvenile Male Wistar rats whose weight ranged between 70–90g each used in this study were procured

from the animal breeder at Iwo, Osun State, Nigeria. The rats were transported in the cool hour of the day to

the research animal house of the Anatomy Department, University of Ilesa, Ilesa, Osun State, Nigeria. The

rodents were housed in metal cages with dimensions 25 × 10 × 10 inches under a temperature-controlled

(22.5°C ± 2.5°C) arena with switched-on lights at 7.00 in the morning. Animals were allowed to feed and drink

clean water ad libitum. Animals were acclimatized for seven days before the commencement of the study.

Research ethical approval was obtained from the research ethical committee of the Faculty of Basic Medical

Sciences, Obafemi Awolowo University, Ile-Ife, Nigeria, with approval number (IPH/OAU/12/3121). All

procedures were carried out in compliance with the approved protocols of the same and within the guidance for

animal care and use prescribed in the scientific procedures on living animals, European Council Directive

(EU2010/63). Ethical approval.

Diets

From weaning and throughout the experimental period, rats in all groups were fed rodent pellets (29% protein,

Page 769

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

11% fat, 58% carbohydrate) procured from a commercial vendor in Ilesa, Osun State, Nigeria.

EXPERIMENTAL METHODOLOGY

Thirty-two (32) Juvenile male Wistar rats were randomly assigned into four groups of eight (n=8) animals per

group. 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 b.w. of rats as previously administered by Salami et al., 2023 (13)

Additionally, groups C and D received fluoxetine at 10mg/kg body weight (14) orally by gavage using an oral

cannula. The substances were administered for five (5) days a week for eight (8) weeks. Twenty-four (24)

hours after the last administration in the eighth week, the rats were transferred to the neurobehavioral room

within the research animal house for assessment of motor coordination using the catalepsy bar test, anxiety-

related behaviours using the elevated plus maze model, and sociability using the three-chamber social

interaction paradigm.

Feed intake and Body weight assessment

Relative feed intake and Body weight were measured daily and weekly, respectively, by an electronic weighing

balance as previously done by García et al. (2013) (15) and Ojo et al. (2025) (16). The relative change in body

weight as measured in this study was calculated for each of the animals using the following equation. The

values for all animals were computed to determine the statistical mean.

Final body weight − Initial body weight

Initial body weight

Behavioral tests

The behavioral tests were done as follows: The catalepsy test, the anxiety-related behaviors with the elevated

plus maze, and the Sociability test using the three-chamber social interaction paradigm. The behavioral assays

were done under a dim light in a room temperature of 25ꢀ±ꢀ2°C within the period of 4 days consecutively,

running each assay on each day in the order stated above. Animals were habituated to the assay room

30 minutes before the evaluation (17).

The Catalepsy Measurement

As previously discussed by Onaolapo et al. (2012) (18) and Luciani et al. (2020) (19), the catalepsy was

measured by lifting the animals and placing their front paws on an elevated steel bar measuring 15cm long,

15mm in diameter, 5.5cm above the surface, with the hind limb above the surface. The centre of the steel bar

was marked to ensure rats were placed at the same position throughout the test. For many rats that refused to

stay in position, the tests were repeated three times, and the cataleptic score was recorded as zero for rats that

were unable to move after several trials. Sixty (60) seconds was considered the end time for animals that

remained on a spot for a longer time. Generally, the experiment is terminated for each animal when one or two

of its forelimbs are removed from the bar. The time of such events was documented, after which the rats were

returned to their respective home cage in preparation for the next test

Anxiety-related Behaviors

The anxiety-related behavior was assessed using the elevated plus-maze, a plus-shaped paradigm that has two

open arms measuring 50 × 10 × 0 cm transversing one another and right-angled to two closed arms that

measure 45 × 10 × 25 cm, with a midpoint area measuring 10 × 10 × 1 cm. The closed arms have two enclosed

walls measuring 30 cm high. Each rat was placed at the midpoint of the maze, facing the closed arm, and the

time spent in either of the closed or open arms was measured for 10 minutes per animal, as previously done by

Onaolapo et al. (2023) (18). The animal is considered to be in the closed arm when the fore and hind limbs

cross into the closed chamber and vice versa.

Page 770

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

Sociability Test

The sociability test was carried out using the three-chamber social interaction paradigm as previously reported

by Szabó et al. (2024) (17) and Onaderu et al. (2025) (20). The sociability paradigm is made of a plastic

container measuring 60 cmꢀ×ꢀ40 cmꢀ×ꢀ20 cm with an exposed upper surface; the chamber is compartmentalized

into three chambers measuring 20 cmꢀ×ꢀ40 cmꢀ×ꢀ20 cm. The three chambers were connected by an entryway

through which the experimental animals could freely move from one chamber to the other. Each of the

experimental animals was habituated to the paradigm for five (5) minutes before the commencement of the

test. A new rat of the same strain and sex (social stimulus) was positioned in a 10 cm diameter wire cylinder-

shaped cup on a side in one of the chambers. The 10 cm diameter wire cylinder-shaped cup was alternated per

trial to avoid bias of a side. A similar but empty diameter wire cylinder-shaped cup (Non-social stimulus) was

positioned in an opposite chamber. The experimental rats were left to explore the apparatus without obstacles

for ten (10) minutes. The total time spent interacting with either the empty wire cylinder-shaped cup, the

neutral middle chamber, or the diameter wire cylinder-shaped cup containing the social-stimulus rat was

recorded and scored. A proximity of less than one cm (< 1 cm) of the experimental animal’s nose oriented

towards the diameter of the wire cylinder-shaped cup is considered an interaction.

Statistical analysis

Chris Rorden’s ANOVA for Windows (version 0.98) was used to analyze data. The analysis was done by One-

way analysis of variance (ANOVA) followed by post-hoc test (Tukey HSD) for intra- and inter-group

comparisons. Results were presented as mean ± S.E.M. The significant difference from the control group was

accepted as p < 0.05.

RESULTS

Effects of Ascorbic Acid on Feed Intake in Fluoxetine-Treated Rats.

Figure 1 shows the effects of ascorbic acid on the daily feed intake in rats treated with fluoxetine. A

statistically significant decrease (p < 0.05) was observed in the group that received fluoxetine compared to the

control group. Compared to the fluoxetine-treated group (C), a statistically significant increase (p < 0.05) was

observed in the group co-administered fluoxetine and ascorbic acid (D).

Figure 1: Effect of ascorbic acid on the daily feed intake in rats treated with fluoxetine. Each bar represents

Mean ± S.E.M., with p < 0.05 against control. bp < 0.05 represents a significant difference from FXT; the

number of rats per treatment group, n=8. FXT: fluoxetine, AsA: ascorbic acid.

Effects of Ascorbic Acid on Body Weight in Fluoxetine-Treated Rats.

Figure 2 shows the effects of ascorbic acid on the relative change in body weight in rats treated with

fluoxetine. A statistically significant decrease (p < 0.05) was observed in the group that received fluoxetine

alone (C) compared to the control group (A). Compared to the fluoxetine-treated group (C), a statistically

significant increase (p < 0.05) was seen in the group co-administered fluoxetine and ascorbic acid (D).

Page 771

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

Figure 2: Effect of ascorbic acid on the relative body weight change in rats treated with fluoxetine. Each bar

b

represents Mean ± S.E.M., with p < 0.05 against control. p < 0.05 represents a significant difference from

FXT; the number of rats per treatment group = 8. FXT: fluoxetine, AsA: ascorbic acid.

Effects of Ascorbic Acid on Motor Coordination on the Catalepsy Bar Test in Fluoxetine-Treated Rats.

Figure 3 shows the effects of ascorbic acid on motor coordination on the catalepsy bar test in rats treated with

fluoxetine. A statistically significant increase (p < 0.05) was noted in the group that received fluoxetine alone

(C) compared to the control group (A). Compared to the fluoxetine-treated group (C), a statistically significant

decrease (p < 0.05) was seen in the group co-administered fluoxetine and ascorbic acid (D).

Figure 3: Effect of ascorbic acid on catalepsy in rats treated with fluoxetine. Each bar represents Mean ±

a

b

S.E.M., with p < 0.05 against control. p < 0.05 represents a significant difference from FXT; the number of

rats per treatment group = 8. FXT: fluoxetine, AsA: ascorbic acid.

Effects of Ascorbic Acid on Anxiety-Related Behaviors in Fluoxetine-Treated Rats.

Figure 4 shows the effects of ascorbic acid on time spent in the open arm in rats treated with fluoxetine. Sole

administration of ascorbic acid in group B was associated with a statistically significant increase (p < 0.05)

compared to the control group. A statistically significant decrease was observed in the fluoxetine-treated group

(C) compared to the control (A) and the ascorbic acid-administered group (B). Moreover, co-administration of

fluoxetine and ascorbic acid in group D was associated with a statistically significant increase (p < 0.05) in the

time spent in the open arm compared to group D.

Page 772

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

Figure 4: Effect of ascorbic acid on the time spent in the open arm in rats treated with fluoxetine. Each bar

a

b

represents Mean ± S.E.M., with p < 0.05 against control. p < 0.05 represents a significant difference from

FXT; the number of rats per treatment group n=8. FXT: fluoxetine, AsA: ascorbic acid.

Figure 5 shows the effects of ascorbic acid on time spent in the closed arm in rats treated with fluoxetine. Sole

administration of ascorbic acid in group B was associated with a statistically significant decrease (p < 0.05)

compared to the control group. A statistically significant increase was observed in the fluoxetine-treated group

(C) compared to the control (A) and the ascorbic acid-administered group (B). Moreover, co-administration of

fluoxetine and ascorbic acid in group D was associated with a statistically significant decrease (p < 0.05) in the

time spent in the open arm

Figure 5: Effect of ascorbic acid on the time spent in the closed arm in rats treated with fluoxetine. Each bar

a

b

represents Mean ± S.E.M., with p < 0.05 against control. p < 0.05 represents a significant difference from

FXT; the number of rats per treatment group, n=8. FXT: fluoxetine, AsA: ascorbic acid.

Effects of Ascorbic Acid on sociability in fluoxetine-treated rats.

Figure 6 shows the effects of ascorbic acid on the interaction time in seconds (s) with the empty chamber and

social stimulus (a strange rat) in rats treated with fluoxetine. On the empty chamber interaction, a statistically

significant increase (p < 0.05) was observed in the fluoxetine-treated group (C) compared to the control (A),

while the co-administration of fluoxetine and ascorbic acid in group D was associated with a statistically

significant decrease (p < 0.05) in the interaction time with the empty chamber. Moreover, during the time spent

with the social stimulus, a statistically significant decrease was observed in the fluoxetine-treated group (C)

compared to the control (A) and the ascorbic acid-administered group (B). However, the co-administration of

fluoxetine and ascorbic acid in group D was associated with a statistically significant increase (p < 0.05) in the

interaction time with social stimulus compared to group C.

Page 773

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

Figure 6: Effect of ascorbic acid on the interaction time with the empty chamber and the social stimulus in

fluoxetine treated rats. Each bar represents Mean ± S.E.M. The number of rats per treatment group, n=8. FXT:

fluoxetine, AsA: ascorbic acid.

Figure 7 shows the effects of ascorbic acid on the number of interactions between the rats treated with

fluoxetine and the social stimulus. A statistically significant decrease (p < 0.05) was observed in the fluoxetine-

treated group (C) compared to the groups A and B, while the co-administration of fluoxetine and ascorbic acid

in group D was associated with a statistically significant increase (p < 0.05) compared to group C.

Figure 6: Effect of ascorbic acid on the interaction time with the empty chamber and the social stimulus in

a

fluoxetine treated rats. Each bar represents Mean ± S.E.M. with p < 0.05 against control. ^bp < 0.05 represents

a significant difference from FXT. The number of rats per treatment group, n=8. FXT: fluoxetine, AsA:

ascorbic acid.

DISCUSSION

The impact of fluoxetine on daily feed intake, relative change in body weight, catalepsy score (a measure of

muscular rigidity and the inability to correct an externally imposed abnormal posture), time spent in the open

arm, and closed arm of the elevated plus maze, as well as the sociability, was evaluated.

Administration of the commonly prescribed antidepressant drug in this study shows some debilitating effects,

as seen with the significant decrease in daily feed intake and loss of body weight in the group solely

administered fluoxetine. While this result is in corroboration with clinical trials that reported similar effects

(21), it has not been documented as a threat to human health in clinical trials. However, an extended and

unmonitored significant loss of appetite and weight loss could further result in other complications, such as

Page 774

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

fatigue and dizziness, as well as other psychological effects (22). The calorie deficit, often resulting from loss

of appetite, is a justification for the accompanied weight loss in the same group. Interestingly, the ameliorative

effects of ascorbic acid were observed in this study, with both the daily feed intake and relative change in body

weight being significantly increased in the group that was co-administered fluoxetine and Ascorbic acid.

Furthermore, the catalepsy score, a measure of muscular rigidity as examined in this study, reveals an

association between the fluoxetine usage and muscular rigidity, with the catalepsy score significantly

increasing with its sole administration. Fluoxetine’s ability to inhibit calcium entry further interferes with the

calcium signal, which alters muscle tone and contractility (23). While fluoxetine does not directly deplete

striatal dopamine levels, its usage is known to exacerbate decreased striatal dopamine activities (24). A

bidirectional relationship exists between dopamine metabolism and oxidative stress; dopamine metabolism

generates reactive oxygen species, a hallmark of oxidative stress (25). While fluoxetine is commonly known to

reverse oxidative stress in clinical trials and animal studies (26), its chronic administration is shown to induce

oxidative stress in animal studies (27). However, the alleviating impact of Ascorbic acid was appreciated with

the decreased catalepsy score in the group that received both fluoxetine and Ascorbic acid. Study done by

Zylinska. (2023) (28) shows that Ascorbic acid can modulate calcium signaling, a major process that was

deregulated by fluoxetine usage. It is known that Ascorbic acid can inhibit and facilitate calcium signaling

depending on beneficial calcium levels. Furthermore, ascorbic acid, a dopamine β-hydroxylase cofactor,

indirectly enhances dopamine synthesis and also modulates dopamine levels through its antioxidant properties

(29). The results of the anxiety-related behaviours as observed with the time spent in the open and closed arms

in this study contrast with some studies that reported the anxiolytic effects of fluoxetine. (30) Acute fluoxetine

administration rapidly blocks serotonin reuptake, spiking extracellular 5-HT within one hour in animal models,

eliciting anxiogenic effects before adaptations (31). Panicogenic effects observed with chronic fluoxetine

administration in this study contrast with the established anxiogenic effects that are associated with its acute

administration. On the other hand, the result of this study is in tandem with the findings that established an

anxiogenic effect of fluoxetine usage as a symptom of its onset of action, although in acute administration (32).

Administration of fluoxetine was associated with a significant decrease in the time spent in the open arm,

while the increases significant in time spent in the closed arm; these effects were reversed with Ascorbic acid

usage. This result raises a controversy as regards the beneficial effects of fluoxetine in this context. Loss of

appetite and weight loss observed with fluoxetine usage could be a contributing factor to the anxiogenic traits

seen with its administration, as studies have continued to establish a linkage between loss of appetite and

psychological derailment, such as emotional distress and depression (33,34).

Although it was interesting to note that depression is not solely a result of loss of appetite, but an outcome of

multiple interplays between decreased feed intake and some biological mechanisms that exacerbate wellness. A

complex multifactorial impact on sociability test has been documented concerning the fluoxetine usage; (3)

their study shows that acute administration of fluoxetine was associated with social avoidance and vigilance,

and conversely increases sociability under acute administration, particularly under stress conditions. The time

spent with the social stimulus, empty chamber, and the interaction count with the social stimuli all reveal

exacerbated effects of fluoxetine on social interaction. On the other hand, ascorbic acid mitigated these effects

by enhancing the sociability in rats co-administered ascorbic acid and fluoxetine.

CONCLUSION

This study reveals the debilitating effects of fluoxetine administration on daily feed intake, relative change in

body weight, catalepsy test, anxiety-related behaviors, and sociability in the treatment of depressive disorder.

Although its usage is generally considered safe in clinical trials, except about its well-established adverse

effects on sperm health. Several instances have been seen where a drug that has been considered safe was

banned due to repeated reports of its adverse effects. Could there be a complex interplay that underlies its yet-

approved adverse effects as seen in this study?

Further research is necessary to evaluate and ascertain the chronic and acute administration of fluoxetine,

particularly on the anxiety-related behaviours; such findings will be more precise if the levels of some key

oxidative stress markers and the histomorphology of brain regions for mood and sociability are evaluated.

Moreover, translation of these effects to humans will require further studies.

Page 775

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

Conflict of Interest

The authors declared none

ACKNOWLEDGEMENTS

None

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

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

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

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

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

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

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

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

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

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

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

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.

https://doi.org/10.3934/Neuroscience.2022014

13. 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

Page 776

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

14. 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.

https://doi.org/10.7860/JCDR/2017/26958.9953

15. 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

16. 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

17. 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.

18. 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.

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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.

https://doi.org/10.3390/antiox12020231

29. 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.

https://doi.org/10.1016/j.freeradbiomed.2008.12.018

30. 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.

https://doi.org/10.1016/j.jsps.2015.03.006

Page 777

www.rsisinternational.org

INTERNATIONAL JOURNAL OF RESEARCH AND SCIENTIFIC INNO V A T ION (IJRSI)

ISSN No. 2321-2705 | DOI: 10.51244/IJRSI |V o lume XII Issue XI November 2025

31. 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.

https://doi.org/10.1371/journal.pone.0295280

32. 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

33. 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

34. 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

Page 778

www.rsisinternational.org