The Psychological Effects of Rapid Aeromedical Evacuation in a Predator Exposure Animal Model of Post-Traumatic Stress Disorder.

Recent conflicts have contributed to an escalation in combat-related psychiatric disorders, including post-traumatic stress disorder (PTSD). Although technological advances have increased the speed from which battlefield injuries reach definitive care, mental health conditions have continued to rise. This study sought to analyze the effects of flight stressors and the lack of a postcombat decompression period on stress-related behavior. We hypothesized that a 1-week decompression period before flight would attenuate stress-related behavior compared to no decompression. PTSD-like effects were induced in male Sprague-Dawley rats. The rats were placed in cages with a cat on two occasions during the 31-day stress regimen. PTSD rats were also subjected to daily cage cohort changes. At the conclusion of the stress regimen, the animals were flown on a military aircraft (WC-130J) for 4 hours. They were subsequently tested via elevated plus-maze and fear conditioning system. The PTSD animals that experienced a decompression period demonstrated decreased anxiety as compared to the no decompression group. In contrast, no difference was noted between the non-PTSD decompression and no decompression flight and no flight groups. The decrease in anxiety between the PTSD flight groups suggests that a decompression period before evacuation may minimize the potential for PTSD development.

The Anti-Inflammatory Effects of Blueberries in an Animal Model of Post-Traumatic Stress Disorder (PTSD).

Post-traumatic stress disorder (PTSD) is a trauma and stressor-related disorder that results in a prolonged stress response. It is associated with increased oxidative stress and inflammation in the prefrontal cortex (PFC) and hippocampus (HC). The only approved therapy for PTSD is selective serotonin re-uptake inhibitors (SSRIs), but their efficacy is marginal. Recently, we demonstrated that over-production of norepinephrine (NE) as the possible reason for the lack of efficacy of SSRIs. Hence, there is a need for novel therapeutic approaches for the treatment of PTSD. In this study, we investigated the anti-inflammatory role of blueberries in modulating inflammatory markers and neurotransmitter levels in PTSD. Rats were fed either a blueberry enriched (2%) or a control diet. Rats were exposed to cats for one hour on days 1 and 11 of a 31-day schedule to simulate traumatic conditions. The rats were also subjected to psychosocial stress via daily cage cohort changes. At the end of the study, the rats were euthanized and the PFC and HC were isolated. Monoamines were measured by high-performance liquid chromatography. Reactive oxygen species (ROS), gene and protein expression levels of inflammatory cytokines were also measured. In our PTSD model, NE levels were increased and 5-HT levels were decreased when compared to control. In contrast, a blueberry enriched diet increased 5-HT without affecting NE levels. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also studied and they confirmed our findings. The enhanced levels free radicals, gene and protein expression of inflammatory cytokines seen in the PTSD group were normalized with a blueberry enriched diet. Decreased anxiety in this group was shown by improved performance on the elevated plus-maze. These findings indicate blueberries can attenuate oxidative stress and inflammation and restore neurotransmitter imbalances in a rat model of PTSD.

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

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.

Valproic acid effects in the hippocampus and prefrontal cortex in an animal model of post-traumatic stress disorder.

Reactive oxygen species (ROS) and pro-inflammatory cytokines (PIC) are upregulated in post-traumatic stress disorder (PTSD). Histone deacetylase inhibitors (HDACi) modify genetic transcription and can diminish ROS and PIC escalation. They can also modulate levels of neurotransmitters such as catecholamines and serotonin (5-HT). Thus, this study sought to analyze the effects of the HDACi valproic acid (VA) on oxidative stress, inflammation, and neurotransmitter modulation via a predator exposure/psychosocial stress animal model of PTSD. 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 1h on days 1, 11, and 40 of a 40-day stress regimen. PTSD rats were also subjected to psychosocial stress via daily cage cohort changes. At the conclusion of the stress regimen, the treatment group (PTSD+VA) and control group (Control+VA) rats were given VA in their drinking water for 30 days. The rats were then euthanized and their brains were dissected to remove the hippocampus and prefrontal cortex (PFC). Whole blood was collected to assess systemic oxidative stress. ROS and PIC mRNA and protein elevation in the PTSD group were normalized with VA. Anxiety decreased in this group via improved performance on the elevated plus-maze (EPM). No changes were attributed to VA in the control group, and no improvements were noted in the vehicle groups. Results indicate VA can attenuate oxidative stress and inflammation, enhance fear extinction, and correct neurotransmitter aberrancies in a rat model of PTSD.

Predator exposure/psychosocial stress animal model of post-traumatic stress disorder modulates neurotransmitters in the rat hippocampus and prefrontal cortex.

Post-Traumatic Stress Disorder (PTSD) can develop in response to a traumatic event involving a threat to life. To date, no diagnostic biomarkers have been identified for PTSD. Recent research points toward physiological abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, sympathoadrenal medullary and immune system that may be implicated in the disorder. The modulation of neurotransmitters is another possible mechanism, but their role in the progression of PTSD is poorly understood. Low serotonin (5-HT) may be a factor, but it may not be the only neurotransmitter affected as modulation affects levels of other neurotransmitters. In this study, we hypothesized the predator exposure/psychosocial stress rodent model of PTSD may alter levels of 5-HT and other neurotransmitters in the rat hippocampus and prefrontal cortex (PFC). Male Sprague-Dawley rats were used in this experiment. We induced PTSD via a predator exposure/psychosocial stress model, whereby rats were placed in a cage with a cat for 1 hour on days 1 and 11 of the 31-day experiment. Rats also received psychosocial stress via daily cage cohort changes. On day 32, the rats were sacrificed and the brains dissected to remove the hippocampus and PFC. Norepinephrine (NE), 5-Hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), dopamine (DA), and 3,4-Dihydroxyphenylacetic acid (DOPAC), and 5-HT levels in the hippocampus and PFC were measured with high-performance liquid chromatography (HPLC). In the hippocampus, 5-HT and HVA were lower, while NE and DOPAC were higher, in the PTSD group vs. controls. In the PFC, only 5-HT was lower, while NE, DA, and DOPAC were higher, in the PTSD group vs. controls. The rate limiting enzymes tyrosine hydroxylase and tryptophan hydroxylase were also examined and confirmed our findings. These results demonstrate that the predator exposure/psychosocial stress model of PTSD produces neurotransmitter changes similar to those seen in human patients and may cause a heightened noradrenergic response.

Inflammation and oxidative stress are elevated in the brain, blood, and adrenal glands during the progression of post-traumatic stress disorder in a predator exposure animal model.

This study sought to analyze specific pathophysiological mechanisms involved in the progression of post-traumatic stress disorder (PTSD) by utilizing an animal model. To examine PTSD pathophysiology, we measured damaging reactive oxygen species and inflammatory cytokines to determine if oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation were upregulated in response to constant stress. Pre-clinical PTSD was induced in naïve, male Sprague-Dawley rats via a predator exposure/psychosocial stress regimen. PTSD group rats were secured in Plexiglas cylinders and placed in a cage with a cat for one hour on days 1 and 11 of a 31-day stress regimen. In addition, PTSD group rats were subjected to psychosocial stress whereby their cage cohort was changed daily. This model has been shown to cause heightened anxiety, exaggerated startle response, impaired cognition, and increased cardiovascular reactivity, all of which are common symptoms seen in humans with PTSD. At the conclusion of the predator exposure/psychosocial stress regimen, the rats were euthanized and their brains were dissected to remove the hippocampus, amygdala, and pre-frontal cortex (PFC), the three areas commonly associated with PTSD development. The adrenal glands and whole blood were also collected to assess systemic oxidative stress. Analysis of the whole blood, adrenal glands, and brain regions revealed oxidative stress increased during PTSD progression. In addition, examination of pro-inflammatory cytokine (PIC) mRNA and protein demonstrated neurological inflammatory molecules were significantly upregulated in the PTSD group vs. controls. These results indicate oxidative stress and inflammation in the brain, adrenal glands, and systemic circulation may play a critical role in the development and further exacerbation of PTSD. Thus, PTSD may not be solely a neurological pathology but may progress as a systemic condition involving multiple organ systems.