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. 2023 Jan 16;19(1):1.
doi: 10.1186/s12993-023-00204-z.

Effect of combination fluoxetine and exercise on prefrontal BDNF, anxiety-like behavior and fear extinction in a female rat model of post-traumatic stress disorder (PTSD): a comparison with male animals

Sakineh Shafia  1 , Farkhonde Nikkhah  2 , Kobra Akhoundzadeh  3
Affiliations

Effect of combination fluoxetine and exercise on prefrontal BDNF, anxiety-like behavior and fear extinction in a female rat model of post-traumatic stress disorder (PTSD): a comparison with male animals

Sakineh Shafia et al. Behav Brain Funct. .

Abstract

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 combination 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: Exercise; Fluoxetine; PTSD; Single prolonged stress; sex.

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Conflict of interest statement

The authors have no conflicts of interest to disclose that could influence this work.

Figures

Fig. 1
Fig. 1
Timelines of experiments
Fig. 2
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
Fig. 3
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)
Fig. 4
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
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