Differential effects of sertraline in a predator exposure animal model of post-traumatic stress disorder

Abstract

Serotonin (5-HT), norepinephrine (NE), and other neurotransmitters are modulated in post-traumatic stress disorder (PTSD). In addition, pro-inflammatory cytokines (PIC) are elevated during the progression of the disorder. Currently, the only approved pharmacologic treatments for PTSD are the selective-serotonin reuptake inhibitors (SSRI) sertraline and paroxetine, but their efficacy in treating PTSD is marginal at best. In combat-related PTSD, SSRIs are of limited effectiveness. Thus, this study sought to analyze the effects of the SSRI sertraline on inflammation and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. We hypothesized that sertraline would diminish inflammatory components and increase 5-HT but might also affect levels of other neurotransmitters, particularly NE. PTSD-like effects were induced in male Sprague-Dawley rats (n = 6/group × 4 groups). The rats were secured in Plexiglas cylinders and placed in a cage with a cat for 1 h on days 1 and 11 of a 31-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, treatment group animals were injected intraperitoneally (i.p.) with sertraline HCl at 10 mg/kg for 7 consecutive days, while controls received i.p. vehicle. The animals were subsequently sacrificed on day 8. Sertraline attenuated inflammatory markers and normalized 5-HT levels in the central nervous system (CNS). In contrast, sertraline produced elevations in NE in the CNS and systemic circulation of SSRI treated PTSD and control groups. This increase in NE suggests SSRIs produce a heightened noradrenergic response, which might elevate anxiety in a clinical setting.

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

“…In particular, in line with the literature and our hypothesis, treatment in a stressful condition overall led to an anti-inflammatory response (Cheng et al, 2016;Ji et al, 2014;Jiang et al, 2013;Lu et al, 2014;Tianzhu et al, 2014;Wilson et al, 2014;Xie et al, 2015). By contrast, fluoxetine treatment in an enriched condition led to an increased expression of inflammatory genes.…”

“…These findings indicate that fluoxetine increases the overall inflammatory milieu in the enriched condition, while exerting an opposite effect in the stressful condition. The latter result is in line with previous studies showing that fluoxetine, when administered to mice exposed to a stressful environment, overall reduces hippocampal expression of pro-inflammatory cytokines (Cheng et al, 2016;Ji et al, 2014;Jiang et al, 2013;Lu et al, 2014;Tianzhu et al, 2014;Wilson et al, 2014;Xie et al, 2015).…”

“…It should also be noted that studies describing antidepressant effects on inflammation, though showing similar overall pro-or anti-inflammatory effects, often report differences in the nature of the individual cytokines affected by treatment. For instance, some studies report a decrease of IL-1β expression following fluoxetine administration in mice exposed to stress (Cheng et al, 2016;Lu et al, 2014), while others do not (Wilson et al, 2014). The variable SSRI effects on cytokine levels have also been described in the peripheral inflammatory markers of depressed patients (Jazayeri et al, 2010;Song et al, 2009).…”

Predator-based psychosocial stress animal model of PTSD: Preclinical assessment of traumatic stress at cognitive, hormonal, pharmacological, cardiovascular and epigenetic levels of analysis

“…In an extension of their VA work, this group also reported that 5-HT levels were normalized with chronic treatment of psychosocially stressed rats with a selective serotonin reuptake inhibitor (SSRI) (Wilson et al, 2014b). Perhaps most important, NE levels remained significantly increased in stressed rats treated with sertraline, which may explain why sertraline provided no benefit in relation to anxiety-like behavior in the stressed rats (Wilson et al, 2014b).…”

“…Perhaps most important, NE levels remained significantly increased in stressed rats treated with sertraline, which may explain why sertraline provided no benefit in relation to anxiety-like behavior in the stressed rats (Wilson et al, 2014b).…”