Fluoxetine treatment is effective in a rat model of childhood-induced post-traumatic stress disorder

Abstract

Although selective serotonin reuptake inhibitors (SSRIs) are first-line treatment for post-traumatic stress disorder (PTSD) patients, their therapeutic efficacy is limited. Childhood adversities are considered a risk factor for developing PTSD in adulthood but may trigger PTSD without additional trauma in some individuals. Nevertheless, just as childhood is considered a vulnerable period it may also be an effective period for preventive treatment. Using a rat model of childhood-induced PTSD, pre-pubertal stress (juvenile stress, JVS), we compared the therapeutic effects of fluoxetine and examined the effectiveness of 1 month of fluoxetine treatment following JVS and into adulthood compared to treatment in adulthood. Since not all individuals develop PTSD following a trauma, comparing only group means is not the adequate type of analysis. We employed a behavioral profiling approach, which analyzes individual differences compared to the normal behavior of a control group. Animals exposed to JVS exhibited a higher proportion of affected animals as measured using the elevated plus maze 8 weeks after JVS. Fluoxetine treatment following the JVS significantly decreased the proportion of affected animals as measured in adulthood. Fluoxetine treatment in adulthood was not effective. The results support the notion that childhood is not only a vulnerable period but also an effective period for preventive treatment.

Fig. 1

Timeline of the experimental design

Fig. 2. A representative figure of the performances of an “affected” animal

Numbers in bold represent this animal’s particular scores. Blue bars represent the animal’s scores that are within normal distribution, while the red bars represent the animal’s scores that deviate from normal distribution. Since 4 out of 7 measures deviate from the normal distribution, this animal was classified as “affected”

Fig. 3. Effects of juvenile stress (JVS) and fluoxetine treatment (FLX) on fluid intake

Fluid intake measured when FLX was given since juvenility (a). Fluid intake measured when FLX was given during adulthood (b). All rats that were treated with FLX had decreased fluid intake compared to all rats that were drinking water, but only when treated during adulthood (p < 0.01). Data expressed in means ± SEM. N since juvenility: control = 10, control + FLXjuv = 9, JVS = 9, JVS + FLXjuv = 16; N during adulthood: control = 17, control + FLXadlt = 12, JVS = 6, JVS + FLXadlt = 12

Fig. 4. Effects of juvenile stress (JVS) and fluoxetine treatment (FLX) on anxiety-like behavior in the elevated plus maze

Total distance covered in the maze (a). Distance anxiety index measured as open / closed arms ratio, with lower ratios indicating higher anxiety levels (b). Duration anxiety index measured as open /closed arms ratio, with lower ratios indicating higher anxiety levels (c). All JVS groups exhibited significantly lower activity level and significantly higher levels of anxiety by both distance and duration indexes, compared to control rats. FLXadlt groups exhibited significantly higher levels of anxiety by both distance and duration indexes, compared to “no FLX” groups, while FLXjuv groups were not significantly different from “no FLX” groups. Data expressed in means ± SEM. N: control = 30, control + FLXjuv = 12, control + FLXadlt = 12, JVS = 31, JVS + FLXjuv = 19, JVS + FLXadlt = 12. *Significant difference compared to control groups, p < 0.05, ***p < 0.001. ^#Significant difference compared to no FLX groups, p < 0.05

Fig. 5. The effects of juvenile stress (JVS) and fluoxetine treatment (FLX) on the distribution of affected and non-affected animals

JVS Rats exhibited significantly higher rates of affected animals compared to controls. Following JVS, only FLXjuv rats exhibited significantly lower rates of affected animals compared to JVS, rates that are similar to the control group. N: control = 30, control + FLXjuv = 12, control + FLXadlt = 12, JVS = 31, JVS + FLXjuv = 19, JVS + FLXadlt = 12. *Significant difference compared to controls, p < 0.05, ***p < 0.001, ^#Significant difference compared to JVS group, p < 0.05