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Despite significant differences between men and women in the symptoms of PTSD and the response to therapeutic interventions, most PTSD studies have been done on male subjects. Continuing our previous study in male rats, this study aimed at better understanding the effect of a combination therapy of exercise with fluoxetine on female PTSD rats. The results were then compared with our past findings in male animals. Female adult Wistar rats subjected to PTSD were treated with moderate treadmill exercise or fluoxetine, or a combination of both. PTSD was induced by the single prolonged stress (SPS) model. Elevated plus-maze (EPM), serum and prefrontal BDNF, and fear extinctions were evaluated. The results showed that exercise plus fluoxetine decreased anxiety-like behavior, improved fear extinction, and increased BDNF changes in female rats. The effects of exercise alone were comparable with those of combina- tion therapy except that combination therapy was more effective on OAT (open arm entry). The majority of results in female rats, except for those of prefrontal BDNF, 4th extinction, and OAT, were similar to those of male rats as shown in our previous study. According to our findings, exercise as a safe and cost-effective intervention can be considered as a complementary efficient option for PTSD treatment in both sexes. To achieve better treatment outcomes in PTSD patient, considering sex differences is recommended. Keywords PTSD, Single prolonged stress, Exercise, Fluoxetine, sex Introduction Women are more susceptible to the experience of PTSD after a traumatic event compared to men . Indeed, they are twice as likely as men to be affected by PTSD . Also, there are significant differences between men and *Correspondence: women in terms of PTSD symptoms and the effects of Kobra Akhoundzadeh firstname.lastname@example.org treatments [3–6]. In spite of sex differences in PTSD, our Immunogenetics Research Center, Department of Physiology, current knowledge of PTSD is mostly based on research Mazandaran University of Medical Sciences, Sari, Iran on males, and not enough attention has been given to Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran assess the effect of sex on traumatic stress . Faculty of Nursing and Midwifery, Qom University of Medical Sciences, Regardless of the several therapeutic approaches for Qom, Iran PTSD, it is still a disorder without satisfying interventions © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 2 of 12 for all cases of patients . For example, it has been with a 12/12 h light–dark cycle, and given ad libitum shown that fluoxetine as a known treatment for PTSD access to water and food. All experiments were per- is not effective in combat veterans with severe, chronic formed in accordance with the Research Ethics Com- PTSD . Moreover, studies revealed that responses to mittee of Mazandaran University of Medical Science treatment with fluoxetine may be different regarding sex (ethical code numbers: IR.MAZUMS.REC.1399.7873, IR. [9, 10]. MAZUMS.4.REC.1400.10267) and the Iran National Anxiety and depression-like behaviors are core symp- Committee for Ethics in Biomedical Research. The ani - toms of PTSD  and exercise has been shown to mals were randomly allocated into 8 groups (each 7–10 have an anti-depressant-like property . Exercise has rats); sham without receiving any intervention (NSPS/ been of interest in the treatment of depressive disorders SED-VEH), sham received fluoxetine (NSPS/SED-FLX), because of its synergistic effect with antidepressants as sham did exercise (NSPS/EXC-VEH), sham received well as being a relatively safe and low-cost intervention fluoxetine and did exercise (NSPS/ EXC-FLX), SPS with - . Based on the anti-depressant-like properties of out receiving any intervention (SPS/SED-VEH), SPS exercise  it seems that the combination of exercise received fluoxetine (SPS/SED-FLX), SPS did exercise with fluoxetine may lead to greater therapeutic effects (SPS/EXC-VEH), SPS received fluoxetine and did exer - on PTSD recovery. It has been shown that a combina- cise (SPS/EXC-FLX). The timeline of research is shown tion of fluoxetine and exercise, but not fluoxetine alone, in Fig. 1. increases neurogenesis in postpartum depression . However, some studies did not confirm whether the com - Single prolonged stress (SPS) induction bination of exercise and anti-depressant would result in As illustrated in our previous study, SPS as a model an augmentative effect or not . Moreover, it seems of PTSD was induced in rats by being faced with three that the effects of exercise are related to the variables stressors in three phases . Briefly, the rat in the first such as exercise intensity [6, 14] and the sex of subjects phase (psychological stressor) was confined in a restrain - . ing cylinder for 2 h, in the second phase (physiological It is asserted that a full understanding of PTSD needs stressor) was forced to swim in a cylindrical container sex differences to be investigated in the responses to for 20 min, and in the third phase (chemical/endocrino- traumatic stress . Since the effects of both fluoxetine logical stressor) was anesthetized with Diethyl ether [9, and exercise on behavior are influenced by sex, the pre - 17]. After SPS induction, rats were left undisturbed for sent study, following our previous research in male rats, 2 weeks. was designed to assess the effect of the combination of exercise and fluoxetine on anxiety-like behavior and cel - lular alteration in female PTSD and to compare present Drug administration results with our past findings in male animals. Fluoxetine hydrochloride (Dr. Abidi Company, Tehran, Iran) in a dose of 10 mg/kg/day was administrated orally Methods and materials for 30 days . The drug was dissolved in drinking water Animals daily. The control groups received water alone. Before Female adult Wistar rats (200–250 g BW) were bred, sup- drug administration, the volume of water consumption plied, and housed at the animal house of Mazandaran was measured for every cage from the water bottle and University of Medical Science, Sari, Iran. Animals were converted to a daily dose per weight (mg/kg body). All kept in a temperature-controlled room (18–24 °C), Fig. 1 Timelines of experiments Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 3 of 12 drug-receiving groups were weighed on the first day of foot shock. Thereafter, the animal was housed in its cage every week. for 24 h, and extinctions were done for 4 days. In extinc- tion phases, the time taken for the animal to enter the Exercise training protocol dark compartment was recorded as the entrance latency. Two weeks after SPS, exercise groups were forced to run There is no shock in this phase. The rat was allowed to on a treadmill. At first, habituation to the treadmill appa - stay in the dark compartment freely for 180 s, and then it ratus was done by walking on the treadmill at the speed was removed back to the home cage. of 3 m/min for 15 min 3 days . After habituation, moderate exercise started. Therefore, rats run on a tread - Serum and prefrontal BDNF measurement mill with a 0-degree incline, at the speed of 10 m/min for On day 49, after the last extinction test, the rats were 30 min daily for 5 days per week for 4 weeks. Rats in sed- deeply anesthetized, then decapitated. The trunk blood entary groups were placed on the switched-off treadmill was centrifuged (4000 g for 20 min) to collect serum. for 5 min once a day . Also, prefrontal cortexes were quickly isolated. Both the serum and prefrontal cortexes were stored at − 80 °C Anxiety‑like behavior test until further analysis . Prefrontal cortex was cut into Elevated plus maze (EPM) is a standard and widely used small pieces and homogenized in phosphate-buffered test to assess anxiety-like behavior in rodents [21–23]. saline (PBS), pH 7.4 by the homogenizer. The homogen - It consists of two open (50 × 10) and two enclosed ate was centrifuged at 10,000×g for 10 min at 4 ℃. Serum (50 × 10 × 40) arms, crossed in the middle perpendicu- and prefrontal cortex BDNF levels were measured by larly to each other, and a central square (10 × 10 cm). the E-Max ELISA method, according to the manufac- The apparatus is placed at a height of 70 cm above the turer’s instruction using Rat BDNF ELISA kits (ZellBio ground. [21, 23]. Rats were gently placed in the neutral GmbH Germany). The absorbance of samples was read at area facing one of the open arms and given 5 min to dis- 450 nm by a micro plate reader (RT-2100 C, Germany) cover the maze. A total of four paws inside of an arm and values calculated according to related standard were used as criteria for entrance. The number of entries curves. The intra- and inter- assay coefficients of varia - into the open arms and the time spent in the open arms tion were < 10% and < 12%, respectively. The sensitivity of were calculated as the indexes of anxiety reduction. Anxi- the assay was 1 pg/ml. Total protein concentration was ogenic effects selectively decrease the open arm entry determined by the Bradford method and bovine serum and/or open arm time and, in contrast, anxiolytic effects albumin (BSA) was used as a standard . Biochemical selectively increase the open arm entry and/or open arm parameters were adjusted based on total protein content. time. All sessions were videotaped by a camera. Statistical analysis Fear extinction test Normality of data was assessed using Kolmogorov– Fear extinction is a component of cognitive flexibility Smirnov test. Data were presented as Mean ± SEM. that is relevant for important psychiatric diseases . ANOVA with Tukey HSD, as a post-hoc, was applied The test was done using shuttle box in a sound-protected to assess the significant difference between the groups. room. Shuttle-box consists of two dark and light com- SPSS software version 22 was used for data analysis and partments (each 30 × 20 × 20 cm) separated by a guil- p < 0.05 was considered as a significant level. lotine door. The compartments were equipped with the grid floor through which an electric shock (3 s, 1 mA, Results 50 Hz) was given. Before the test, free ambulation in the Level of prefrontal and serum BDNF shuttle-box for 5 min was allowed in order to be adapted The findings of the effects of SPS, and treatment on the to the context. The extinction test has two phases: the level of prefrontal BDNF (Fig. 2A), showed a significant conditioning phase and the extinction phase . The treatment effect (F 48 = 35.751, P = 0.0001). A sig- 3, procedure of two phases has been illustrated in our pre- nificant effect of SPS (F 48 = 42.169, P = 0.0001) was 1, vious study . Briefly, the conditioning phase was car - observed. The interaction between SPS and FLX was sig - ried out in 1 day and then the extinction phases were nificant (F 48 = 4.325, P = 0.009). 3, done over 4 consecutive days (extinctions days 1–4). In The level of prefrontal BDNF was higher in Sham/EXC- the conditioning phase, the animal was placed in the light FLX in comparison with that in Sham/SED-VEH, Sham compartment and the latency for entrance into the dark /SED-FLX, or Sham/EXC-VEH (P = 0.0001). There was compartment (the entrance latency) was recorded. After a significant difference between Sham/EXC-VEH and entry into the dark compartment, the animal received a Sham/SED-VEH (P = 0.014), between SPS/SED-VEH and Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 4 of 12 Fig. 2 Prefrontal cortex (A), and serum BDNF (B) in female SPS and sham groups subjected to fluoxetine and treadmill exercise. SPS groups showed reductions in serum and prefrontal cortex BDNF. SPS groups with fluoxetine & treadmill exercise showed increased in serum and Prefrontal cortex BDNF as compared with SPS sedentary groups. A *SPS/SED-VEH vs sham/SED-VEH (P = 0.001). **sham/EXE-VEH (P = 0.014) and sham/FLX –EXC (P = 0.0001) vs sham/SED-VEH. ***sham/FLX-SED and sham/EXE-VEH (P = 0.0001) vs sham/FLX –EXC. ****SPS/SED-VEH vs SPS/EXC-FLX (P = 0.0001), SPS/EXC-VEH (P = 0. 001), SPS/SED-FLX (P = 0.003). *****SPS/EXC-FLX vs sham/FLX –EXC (P = 0.0001). B *SPS/EXC-VEH (P = 0.015) and SPS/EXC-FLX (P = 0.012) vs SPS/SED-VEH Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 5 of 12 Sham/SED-VEH (P = 0.001), and between SPS/EXC-FLX the three factors, treatment (F 18.132, P = 0.0001), 3, 48= and Sham/ EXC-FLX (P = 0.0001). Also. SPS/EXC-FLX SPS (F 16.345, P = 0.0001) and extinction sessions 1, 48= (P = 0.0001), SPS/EXC-VEH (P = 0. 001), SPS/SED-FLX (F 74.689, P = 0.0001) on the entrance latency into 4, 192= (P = 0.003) groups had significantly higher prefrontal the dark box. There were significant interactions among BDNF in comparison with SPS/SED-VEH group. SPS, treatment, and extinction sessions ((F 2.038, 12, 192= The findings of the SPS effects and treatment (Exer - P = 0.023), between treatment and extinctions sessions cise & Fluoxetine) on the level of serum BDNF are illus- (F 5.060, P = 0.0001), and between SPS and extinc- 12, 192= trated in Fig. 2B. A significant effect of treatment was tions sessions (F 3.897, P = 0.005). The interaction 4, 192= observed (F = 4.956, P = 0.004) but not that of SPS (F between SPS and treatment (F 2.259, P = 0.093) was 3, 48 1, 3, 48= = 2.610, P = 0.113). Also, the interaction between SPS not significant. and FLX was not significant (F = 1.778, P = 0.164). In the conditioning phase, SPS/SED-VEH group 3, 48 There was a significant difference between SPS/EXC- showed an increase in the entrance latency time com- VEH and SPS/SED-VEH (P = 0.015) and between SPS/ pared to Sham/SED-VEH (P = 0.001). Also, the entrance EXC-FLX and SPS/SED-VEH (P = 0.012). latency was significantly lower in SPS/EXC-FLX (P = 0.0001) and SPS/EXC-VEH (P = 0.0001) in compari- son to SPS/SED-VEH. There was a significant difference Anxiety‑related behavior between SPS/EXC-FLX and SPS/SED-FLX (P = 0.046). Figure 3A. shows open arm entry (OAT) percentage. In 1st extinction, the latency time significantly Two way ANOVA on OAT percentage revealed a signifi - increased in SPS/SED-FLX than in Sham /SED-FLX cant effect for SPS (F 116.823, P = 0.0001) and treat- 1, 72= (P = 0.002). The latency time significantly decreased ment (F = 32.417, P = 0.0001). However, there was no 3, 72 in SPS/EXC-FLX, (P = 0.0001) and SPS/EXC-VEH significant interaction between SPS and treatment (F 3, (P = 0.007) than in SPS/SED-VEH. 1.318, P = 0.275). According to the results of post-hoc In 2nd extinction, the latency time increased in SPS/ test on the percentage of OAT, there were significant dif - SED-VEH in comparison to Sham/SED-VEH (P = 0.038). ferences between SPS/SED-VEH vs Sham /SED-VEH The significant time reduction was shown in SPS/EXC- (P = 0.002), between SPS/EXC-VEH vs Sham/EXC-VEH FLX (P = 0.0001), SPS/SED-FLX (P = 0.050) and SPS/ (P = 0.0001), and between SPS/EXC-FLX vs Sham/EXC- EXC-VEH (P = 0.001) than in SPS/SED-VEH. FLX (P = 0.0001). Also, the percentage of OAT in Sham/ In 3rd extinction, the latency time increased in EXC-FLX group was significantly different from that SPS/SED-VEH in comparison to Sham/SED-VEH in Sham/SED-FLX (P = 0.004) and Sham /SED-VEH (P = 0.0001). The significant time reduction was shown (P = 0.0001) groups. The difference between SPS/SED- in SPS/EXC-FLX (P = 0.0001), SPS/SED-FLX (P = 0.011) VEH vs SPS/EXC-FLX was significant (P = 0.0001). and SPS/EXC-VEH (P = 0.003) than in SPS/SED-VEH. Data of open arm entry (OAE) number in the EPM In 4th extinction, the latency time increased in are illustrated in Fig. 3B. A three-way ANOVA on the SPS/SED-VEH in comparison to Sham/SED-VEH OAE demonstrated significant main effects of SPS (F 1, (P = 0.0001). The significant time reduction was shown = 74.689, P = 0.0001) and treatment (F = 10.269, 72 3, 72 in SPS/EXC-FLX (P = 0.0001), SPS/SED-FLX (P = 0.050) P = 0.0001). There was no significant interaction between and SPS/EXC-VEH (P = 0.0001) than in SPS/SED-VEH SPS and treatment (F = 1.231, P = 0.305). Between 3, 72 (Fig. 4A). group comparison showed that there was a significant Extinction index results are shown in Fig. 4B. difference in OAE between SPS/ SED-VEH vs Sham/ ANOVA test of extinction index showed a significant SED-VEH (P = 0.0001), SPS/SED-FLX vs Sham/ SED- effect of treatment (F3, 48 = 11.478, P = 0.0001), SPS FLX (P = 0.0001), SPS/EXC-VEH vs Sham/ EXC-VEH (F1, 48 = 10.583, P = 002) and a significant interaction (P = 0.023), and SPS/EXC-FLX vs Sham/EXC-FLX between SPS and treatment (F3 6.303, P = 0.001). (P = 0.0001) groups. Also, there was significant differ - , 48= A comparison between groups showed the extinction ences between SPS/SED-VEH vs SPS/EXC-VEH, SPS/ percentage in SPS/SED-VEH group was lower than in SED-VEH vs SPS/SED-FLX, and between SPS/SED-VEH the sham/SED-VEH group (P = 0.0001). Also extinction vs SPS/EXC-FLX (P = 0.0001). OAE increased in Sham/ percentage in SPS/SED-FLX (P = 0.008), SPS/EXC-VEH EXC-FLX compared to Sham/SED-VEH (P = 0.046) and (P = 0.001) and SPS/EXC-FLX (P = 0.0001) was higher Sham/SED-FLX (P = 0.040). compared to SPS/SED-VEH. Fear conditioning and extinction Fear conditioning and extinction findings are pre - sented in Fig. 4A. A three –way repeated measure- ments ANOVA showed significant effects for each of Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 6 of 12 Fig. 3 Anxiety-like behaviors in SPS rats subjected to fluoxetine and treadmill exercise as assessed in the elevated plus maze. Exercise and fluoxetine combination groups showed reduction in anxiety level in both groups. SPS groups showed reductions in open arm Time (OAT, A) and open arm Entry (OAE, B). A *sham/SED-VEH vs SPS/SED-VEH (P = 0.002). **Sham/EXC-FLX vs sham/SED-VEH (P = 0.0001). ***Sham/EXC-FLX vs Sham/SED-FLX (P = 0.004). ****Sham/EXC-VEH vs SPS/EXC-VEH (P = 0.0001). *****SPS/EXC-FLX vs Sham/EXC-FLX (P = 0.0001). ******SPS/EXC-FLX vs SPS/SED-VEH (P = 0.0001). B *SPS/ SED-VEH vs Sham/ SED-VEH (P = 0.0001). **ham/EXC-FLX vs Sham/ SED-VEH (P = 0.046). ***SPS/ EXC-VEH and SPS/ SED-FLX and SPS/ EXC-FLX (P = 0.0001) vs SPS/ SED-VEH. ****SPS/SED-FLX vs Sham/ SED-FLX (P = 0.0001). *****SPS/EXC-VEH vs Sham/ EXC-VEH (P = 0.023). ******SPS/EXC-FLX vs Sham/ EXC-FLX (P = 0.0001) Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 7 of 12 Fig. 4 Fear conditioning and extinction index in SPS rats subjected to fluoxetine and treadmill exercise as assessed in extinction test. A (Entrance latency time) Exercise and fluoxetine combination groups showed reduction in entrance latency time in both groups. SPS groups showed increased entrance latency time in conditioning phase and in 1th, 2th, 3th, and 4th extinction. In conditioning phase *SPS/SED-VEH vs Sham/ SED-VEH (P = 0.001). **SPS/EXC-FLX and SPS/EXC-VEH vs SPS/SED-VEH (P = 0.0001). In 1th extinction **SPS/EXC-FLX, (P = 0.0001) and SPS /EXC-VEH (P = 0.007) vs SPS /SED-VEH. **SPS/SED-FLX vs Sham/SED-FLX (P = 0.002). In 2th extinction*SPS/SED-VEH vs Sham/SED-VEH (P = 0.038). **SPS/ EXC-FLX (P = 0.0001), SPS/SED-FLX (P = 0.050), and SPS/EXC-VEH (P = 0.001) vs SPS/SED-VEH. In 3th extinction *SPS/SED-VEH vs Sham/SED-VEH (P = 0.0001). **SPS/EXC-FLX (P = 0.0001), SPS/SED-FLX (P = 0.011) and SPS/EXC-VEH (P = 0.003) vs SPS/SED-VEH. In 4th extinction *SPS/SED-VEH vs Sham/SED-VEH (P = 0.0001). **SPS/EXC-FLX (P = 0.0001), SPS/SED-FLX (P = 0.050) and SPS/EXC-VEH (P = 0.0001) vs SPS/SED-VEH. B (Extinction index) *SPS/SED-VEH vs sham/SED-VEH group (P = 0.0001), **SPS/SED-FLX (P = 0.002), SPS/EXC-VEH (P = 0.0001), and SPS/EXC-FLX (P = 0.0001) vs SPS/SED-VEH Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 8 of 12 Discussion behavior, BDNF, fear conditioning, and extinction. Also, The results showed that stress exposure led to the therapeutic interventions resulted in somewhat simi- reduced OAT and OAE percentage as the markers of lar effects on both sexes. Some sex differences included anxiety-like behavior. SPS affected entrance latency in greater effect of combination therapy than monothera - fear conditioning and extinction. Also, stress signifi - pies on prefrontal BDNF in males and a greater efficacy cantly impacted prefrontal BDNF. However, the reduc- of combination therapy than fluoxetine alone on 4th tion in serum BDNF following SPS was not statistically extinction in female rats. Also, unlike male rats, fluox - significant. Fluoxetine lessened SPS-induced alterations etine and exercise did not improve OAT in female rats. in prefrontal BDNF, fear conditioning, and extinction. The findings of our present and past studies  have However, this drug had no significant effect on OAT and been summarized in the Table 1 to more easily compare OAE. Exercise alone or in combination with fluoxetine male and female rats. restored the malevolent effects of SPS on anxiety-like behavior, prefrontal and serum BDNF, fear conditioning, Eec ff ts of exercise, fluoxetine, and a combination and extinction. of both on prefrontal and serum BDNF in female PTSD rats The present study confirmed that SPS is able to induce The results showed that SPS led to the BDNF reduc - anxiety-like behavior and other PTSD-associated altera- tion in the prefrontal cortex in female rats. The findings tions such as BDNF changes and fear conditioning and were similar to that in male PTSD animals in our previ- extinction impairment  in female rats. Comparison ous study . BDNF changes after stress have been fre- between present results with our previous findings have quently reported in several studies [28–31] and our study shown no sex difference in SPS-induced impairments in confirms these findings. Since BDNF has been shown to Table 1 Eec ff ts of fluoxetine, exercise, and the combination of both, in male and females rats, comparison present results with reported data in previous study  Assessed parameter Interventions P value Male Female Prefrontal BDNF Fluoxetine alone (SPS/SED-VEH vs SPS/SED-FLX) 0.019 0.003 Exercise alone (SPS/SED-VEH vs SPS/EXC-VEH) 0.000 0.001 Combination therapy (SPS/SED-VEH vs SPS/EXE-FLX) 0.000 0.000 Combination therapy VS fluoxetine alone (SPS/SED-FLX vs SPS/EXE-FLX) 0.001 0.565 Combination therapy VS exercise alone (SPS/EXC-VEH vs SPS/EXE-FLX) 0.025 0.761 4th extinction Fluoxetine alone (SPS/SED-VEH vs SPS/SED-FLX) 0.000 0.05 Exercise alone (SPS/SED-VEH vs SPS/EXC-VEH) 0.000 0.000 Combination therapy (SPS/SED-VEH vs SPS/EXE-FLX) 0.000 0.000 Combination therapy VS fluoxetine alone (SPS/SED-FLX vs SPS/EXE-FLX) 0.26 0.008 Combination therapy VS exercise alone (SPS/EXC-VEH vs SPS/EXE-FLX) 0.56 0.51 Extinction index Fluoxetine alone (SPS/SED-VEH vs SPS/SED-FLX) 0.000 0.008 Exercise alone (SPS/SED-VEH vs SPS/EXC-VEH) 0.000 0.001 Combination therapy (SPS/SED-VEH vs SPS/EXE-FLX) 0.000 0.000 Combination therapy VS fluoxetine alone (SPS/SED-FLX vs SPS/EXE-FLX) 0.34 0.054 combination therapy VS exercise alone (SPS/EXC-VEH vs SPS/EXE-FLX) 0.75 0.13 OAT% Fluoxetine alone (SPS/SED-VEH vs SPS/SED-FLX) 0.000 0.823 Exercise alone (SPS/SED-VEH vs SPS/EXC-VEH) 0.004 0.528 Combination therapy (SPS/SED-VEH vs SPS/EXE-FLX) 0.001 0.000 Combination therapy VS fluoxetine alone (SPS/SED-FLX vs SPS/EXE-FLX) 1 − 0.004 Combination therapy VS exercise alone (SPS/EXC-VEH vs SPS/EXE-FLX) 1 − 0.019 OAE Fluoxetine alone (SPS/SED-VEH vs SPS/SED-FLX) 0.11 0.063 Exercise alone (SPS/SED-VEH vs SPS/EXC-VEH) 0.001 0.0001 Combination therapy (SPS/SED-VEH vs SPS/EXE-FLX) 0.000 0.000 Combination therapy VS fluoxetine alone (SPS/SED-FLX vs SPS/EXE-FLX) 0.000 0.322 Combination therapy VS exercise alone (SPS/EXC-VEH vs SPS/EXE-FLX) 0.83 0.965 Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 9 of 12 have an essential role in mediating stress-related patho- antidepressants and exercise, BDNF modulation is con- physiological changes in the brain  these findings sidered as one of the involved mechanisms. are expectable. Impairment in fear extinction is a PTSD Although sex differences in the therapeutic effects marker and BDNF has been reported to be involved in of fluoxetine or exercise on BDNF have been reported fear memories in the amygdala, hippocampus, and pre- in some studies [28, 38, 39], in our studies, fluoxetine frontal cortex . Owing to high sensitivity of the pre- or exercise led to similar therapeutic outcomes in both frontal cortex to stress and its modulation role in many sexes. The only sex difference in prefrontal BDNF was behavioral and physiological responses to stress , that the combination of fluoxetine and exercise was more BDNF alterations in the prefrontal cortex after SPS is an potent than monotherapies in male but not in female important finding. rats. Interestingly, the combination of fluoxetine and Comparison between male and female rats showed no exercise was able to enhance prefrontal BDNF to a higher sex difference in BDNF reduction after SPS. Although level than the normal range in male SPS rats (data was some studies such as that of Aykaç revealed that BDNF not shown). In Aykaç and colleagues’ study, the fluoxetine alteration after SPS has sex differences [28, 30], our stud- effects on BDNF were different between the two groups ies showed similar results in prefrontal BDNF between depending on the assessed region of the brain. For exam- male and female rats. This finding was partly in agree - ple, fluoxetine was able to restore BDNF in the female’s ment with the results of a systematic review and meta- hippocampus but not in the male’s. Similar results have analysis study that showed no significant effect of sex on been reported by Mitic and colleagues . Accordingly, peripheral BDFN in PTSD patients . it has been asserted that fluoxetine effects on stressed In Aykaç and colleagues’ study, no significant difference subjects are also in a brain region-specific manner . was found between males and females in cortical BDNF Therefore, it is likely that inconsistency in the results of levels after the social isolation test, however, female rats BDNF in male and female subjects is due to differences in had lower amygdala BDNF than males after the test . the assessed regions of the brain. Based on the mentioned study, it is probable that the dif- In the present study, unlike the prefrontal BDNF, serum ference in findings between males and females originated BDNF did not show a statistically significant difference from the region of the brain collected for BDNF meas- between SPS and non-SPS rats. Due to difficulty in cross - urement. In other words, stress-induced BDNF alteration ing the blood–brain barrier , peripheral BDNF may in the distinct brain parts differs in a sex-dependent man - not be an accurate biomarker to reflect slight alterations ner . Since the prefrontal region has been shown to in brain BDNF . However, according to the results of be one of the involved parts in PTSD, the present study a meta-analysis study , it was probable that measur- assessed prefrontal BDNF and similar results were found ing plasma BDNF instead of serum BDNF would produce in males and females. more conclusive results. Fluoxetine and exercise individually or in combination were able to restore prefrontal BDNF in female animals. Eec ff ts of exercise, fluoxetine, and a combination These findings were similar to those in male animals of both on fear extinction in female PTSD rats . However, there were some sex differences between Deficient fear extinction is considered as one of the hall - males and females in the therapeutic potency of fluoxe - marks of PTSD symptoms and the present study showed tine alone, exercise alone, and the combination of both. that SPS impaired the extinction of conditioned fear in In female PTSD rats, there was no difference between female rats. Entrance latency decreased in all interven- the effect of monotherapies and combination therapy on tion groups, including fluoxetine alone, exercise alone, prefrontal BDNF while in male PTSD rats, combination and fluoxetine plus exercise over time. These results sug - therapy was more potent than monotherapies. gest that both monotherapy and combination therapy It has been shown that both the antidepressant drug were able to facilitate fear memory extinction in female fluoxetine and exercise are able to increase BDNF expres - SPS rats. Comparison between male and female SPS rats sion in the brain exposed to stress [26, 28, 36], and our indicated somewhat similar results in terms of the effec - results are consistent with these findings. In this regard, tiveness of the interventions. However, it is mentionable exercise induces BDNF enhancement during extinc- that in female SPS rats, unlike in males, combination tion consolidation and, consequently, reduces threat therapy showed greater efficacy in reducing entrance expectancies following reinstatement in PTSD . latency on the 4th day than fluoxetine alone. Also, it is asserted that the likely role of drugs such Although some studies showed that stress-exposed as antidepressants on fear extinction improvement is female rats have more disrupted performance in the fear modulated through the BDNF-TrkB system . Taken extinction learning [5, 29], our study did not reveal a dis- together, in studies designed for PTSD treatment with tinct difference between males and females in the impact Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 10 of 12 of interventions, except greater efficacy of combination the need for individualized treatments considering sex therapy than fluoxetine alone in female rats. effects [7, 15, 47, 48]. The present study showed that the interventions were Fluoxetine alone was not able to induce statistically sig- able to enhance BDNF in the prefrontal regions in both nificant improvement in anxiety behavior in female rats, male and female SPS rats. Besides, they improved fear however, it resulted in a subtle increase in OAE and OAT. extinction over time in both sexes. These findings sup - Therefore, it may show a synergic effect if co-adminis - port the documents reporting that the positive effect of trated with other treatments, as this synergic effect was interventions such as exercise on fear extinction learning revealed in combining fluoxetine with exercise. We can is mediated by increasing BDNF [37, 43, 44]. Since BDNF claim the same for exercise alone that slightly increased plays a role in the fear extinction enhancement, target- OAE. Potentiation of the therapeutic effect of fluoxetine ing the impaired extinction in anxiety disorders such as in combination with exercise was also reported in Gobi- PTSD via BDNF signaling may be an important and novel nath and colleagues’ study on postpartum depression way to enhance treatment efficacy . in female rats. Their study showed that fluoxetine aug - There was a slight sex difference in terms of the ther - mented neurogenesis only when combined with exercise apeutic effect of fluoxetine on the 4th extinction, but . Taken together, in some parameters, the greater not the extinction index. The results in female SPS rats therapeutic effects were shown in male SPS rats than in showed that the effect of fluoxetine was satisfying but it female rats. These findings can partly assert sex-specific was less than that of combination therapy. Previous stud- psychopharmacology in psychological disorders. While ies also reported that fluoxetine resulted in a different there were some sex differences in response to fluoxetine effect between male and female groups [9, 10]. alone or exercise alone, combination therapy was able to restore all parameters affected by PTSD in both sexes. Eec ff ts of exercise, fluoxetine, and a combination It is worth mentioning that although some sex differ - of both on anxiety‑like behaviors in female PTSD rats ences in the effect of interventions on stress-exposed sub - PTSD is an anxiety disorder and SPS is known as an valid jects [6, 28] have been reported, the accurate conclusion rodent model of it . The results of EPM tests showed needs to compare intervention-induced changes with the that SPS was able to induce anxiety-like behavior in normal scores in males and females separately. It is prob- female rats. SPS-exposed rats showed fewer entries into able that the baseline score is different in a sex-specific the open arms and lower percentage of open arm time in manner and consequently leads to different final results comparison to non-SPS rats. between males and females. For example, in our study Fluoxetine alone could not show a significant thera - OAT and OAE percentage in sham groups, as the base- peutic effect on anxiety-like behaviors assessed by EPM line scores, were different between males and females in female rats. However, exercise was able to improve the (data was not shown). Regarding these different findings percentage of open arm entries but had no significant in the present study, the changes after SPS induction and effect on the percentage of open arm time in female SPS following intervention have been compared with the base rats. Combination therapy was more potent than mono- scores in each sex separately. therapies and improved both parameters including OAT and OAE in the female rats as it did in male rats. Com- Conclusion parison of the present results with our findings of the In female rats, there was no significant difference previous study showed that fluoxetine alone and espe - between the effects of combination therapy and exer - cially exercise alone led to better effects in male rats than cise alone in SPS-induced deficits except the increased that in females. These results can be supported to some OAT. In male rats, exercise alone showed more potency extent by Whitworth and colleagues’ study that showed and the improved OAT. Therefore, exercise as a safe and active men have significantly lower PTSD symptoms than cost-effective intervention can be considered as a com - active women . Morgan and colleagues’ study showed plementary efficient option for PTSD treatment in both exercise-induced anxiety behaviors in young female mice sexes. Although the majority of findings related to the . Regarding the role of gonadal hormones on the efficacy of treatments were comparable between males stress-related pathways such as the prefrontal cortex– and females, there were some sex differences. Therefore, amygdala pathway , it was not surprising to see some to achieve better outcomes, considering the differences different findings between males and females. Although between genders is recommended in the treatment of the present study has shown many similarities between PTSD patients. male and female rats regarding the effects of treatments, some inconsistent findings support the opinion of the role of sex and hormones on stress management and Shafia et al. Behavioral and Brain Functions (2023) 19:1 Page 11 of 12 3. Hourani L, Williams J, Bray R, Kandel D. Gender differences in the expres- Limitations sion of PTSD symptoms among active duty military personnel. J Anxiety In the present study, we did not determine the phase of Disord. 2015;29:101–8. https:// doi. org/ 10. 1016/j. janxd is. 2014. 11. 007. estrous cycles in female animals. Since the level of sex 4. Shansky RM. Sex differences in PTSD resilience and susceptibility: chal- lenges for animal models of fear learning. Neurobiol Stress. 2015;1:60–5. hormones can influence behavioral and physiological https:// doi. org/ 10. 1016/j. ynstr. 2014. 09. 005. events, the results may be impacted by the hormonal 5. Mazor A, Matar MA, Kaplan Z, Kozlovsky N, Zohar J, Cohen H. Gender- changes of the menstrual cycle. Measurement of BDNF related qualitative differences in baseline and post-stress anxiety responses are not reflected in the incidence of criterion-based PTSD-like was limited to the prefrontal cortex, which, although is behaviour patterns. World J Biol Psychiatry. 2009;10(4–3):856–69. https:// an important structure involved in PTSD, is not the only doi. org/ 10. 1080/ 15622 97070 15613 83. one. Therefore it would have been better to assess other 6. Whitworth JW, SantaBarbara NJ, Nosrat S, LaBrec JE, Louie ME, Ciccolo JT. Exercise behavior and gender-related differences in posttraumatic stress brain structures involved, such as the hippocampus, for disorder symptoms. Psychol Sport Exerc. 2017;33:18–23. https:// doi. org/ more convincing results in female PTSD. Moreover, we 10. 1016/j. psych sport. 2017. 07. 008. did not analyze the correlation between behavioral and 7. Pooley AE, Benjamin RC, Sreedhar S, Eagle AL, Robison AJ, Mazei-Robison MS, et al. Sex differences in the traumatic stress response: PTSD symp - molecular data due to a large number of tests. These limi - toms in women recapitulated in female rats. Biol Sex Differ. 2018;9(1):1– tations should be considered in future studies. 11. https:// doi. org/ 10. 1186/ s13293- 018- 0191-9. 8. Krystal JH, Davis LL, Neylan TC, Raskind MA, Schnurr PP, Stein MB, et al. It is Acknowledgements time to address the crisis in the pharmacotherapy of posttraumatic stress The authors would like to thank Mazandaran University of Medical Sciences, disorder: a consensus statement of the PTSD psychopharmacology work- Sari, Iran for providing facilities for this work. This paper extracted from the ing group. Biol Psychiatry. 2017;82(7):e51–e9. http:// www. elsev ier. com/ MD student’s thesis of Farkhonde Nikkhah (number: 3678) was financially open- access/ userl icense/ 1.0/. supported by Vice Chancellor for Research Centers of Mazandaran University 9. Hertzberg MA, Feldman ME, Beckham JC, Kudler HS, Davidson JR. Lack of of Medical Sciences, Sari, Iran (Grant Number: 7873). efficacy for fluoxetine in PTSD: a placebo controlled trial in combat vet - erans. Ann Clin Psychiatry. 2000;12(2):101–5. https:// doi. org/ 10. 1023/A: Author contributions 10090 76231 175. KA wrote the main manuscript text. FN gathered data. SS analyzed the data. 10. Pawluski JL, Rayen I, Niessen N-A, Kristensen S, van Donkelaar EL, All authors reviewed the manuscript. All authors read and approved the final Balthazart J, et al. Developmental fluoxetine exposure differentially alters manuscript. central and peripheral measures of the HPA system in adolescent male and female offspring. Neuroscience. 2012;220:131–41. https:// doi. org/ 10. Funding 1016/j. neuro scien ce. 2012. 06. 034. This work was supported by grants from the Mazandaran University of Medi- 11. Patki G, Li L, Allam F, Solanki N, Dao AT, Alkadhi K, et al. Moderate treadmill cal Sciences, Sari, Iran, record no: 7873. exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder. Physiol Behav. 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Behavioral and Brain Functions – Springer Journals
Published: Jan 16, 2023
Keywords: PTSD; Single prolonged stress; Exercise; Fluoxetine; sex
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