Intermittent hypoxia improves behavioral and adrenal gland dysfunction induced by posttraumatic stress disorder in rats

Abstract

Nonpharmacological treatments of stress-induced disorders are promising, since they enhance endogenous stress defense systems, are free of side effects, and have few contraindications. The present study tested the hypothesis that intermittent hypoxia conditioning (IHC) ameliorates behavioral, biochemical, and morphological signs of experimental posttraumatic stress disorder (PTSD) induced in rats with a model of predator stress (10-day exposure to cat urine scent, 15 min daily followed by 14 days of stress-free rest). After the last day of stress exposure, rats were conditioned in an altitude chamber for 14 days at a 1,000-m simulated altitude for 30 min on day 1 with altitude and duration progressively increasing to 4,000 m for 4 h on day 5. PTSD was associated with decreased time spent in open arms and increased time spent in closed arms of the elevated X-maze, increased anxiety index, and increased rate of freezing responses. Functional and structural signs of adrenal cortex degeneration were also observed, including decreased plasma concentration of corticosterone, decreased weight of adrenal glands, reduced thickness of the fasciculate zone, and hydropic degeneration of adrenal gland cells. The thickness of the adrenal fasciculate zone negatively correlated with the anxiety index. IHC alleviated both behavioral signs of PTSD and morphological evidence of adrenal cortex dystrophy. Also, IHC alone exerted an antistress effect, which was evident from the increased time spent in open arms of the elevated X-maze and a lower number of rats displaying freezing responses. Therefore, IHC of rats with experimental PTSD reduced behavioral signs of the condition and damage to the adrenal glands. NEW & NOTEWORTHY Intermittent hypoxia conditioning (IHC) has been shown to be cardio-, vaso-, and neuroprotective. For the first time, in a model of posttraumatic stress disorder (PTSD), this study showed that IHC alleviated both PTSD-induced behavioral disorders and functional and morphological damage to the adrenal glands. Also, IHC alone exerted an antistress effect. These results suggest that IHC may be a promising complementary treatment for PTSD-associated disorders.

Intermittent Hypoxic Conditioning Alleviates Post-Traumatic Stress Disorder-Induced Damage and Dysfunction of Rat Visceral Organs and Brain

“…In stressed PTSD+IHC rats, AI was decreased compared to that of PTSD rats, i.e., IHC produced significant protection from PTSD. This result confirms our earlier study [18]. In that earlier study, we performed the X-maze test to demonstrate that PTSD did not develop in the IHC rats exposed to predator stress in contrast to non-IHC rats exposed to the same stress.…”

“…IHC preconditioning [16] and postconditioning [17] were shown to abolish development of stress-induced anxiety in the rat "stress-restress" model of PTSD. Recently we found that rats treated with IHC prior to predator stress exhibited significantly less anxiety-like behavior, a lesser drop of plasma corticosterone, and reduced structural signs of adrenal gland dystrophy, all signs characteristic of PTSD [18]. In fact, IHC exerted a robust anti-stress effect in naïve rats, as evidenced from less anxiety during an elevated X-maze test [18].…”

Chronic predator scent stress alters serotonin and dopamine levels in the rat thalamus and hypothalamus, respectively

“…The decrease in animals AI after chronic PSS, observed two weeks after the last exposure to the stressor, is similar to this reported in our previous studies (Lazuko et al 2018;Manukhina et al 2018). Our funding on the altered 5-HT transmission in the thalamus is consistent with previous studies by other groups.…”

“…Repeated exposure of the rats to the predator scent stress (PSS) has been used in our previous studies as an animal model of post-traumatic stress disorder (PTSD). We had previously reported that repeated PSS induce long-lasting behavioral changes, such as increased anxiety index (AI), observed as late as fourteen days after the last PSS exposure (Lazuko et al 2018;Manukhina et al 2018). Repeated PSS might be a more accurate model for PTSD than the acute one, since it minimizes the effect of uncontrolled factors, such as concentration of pheromones in each individual dose of urine.…”

Post-Traumatic Stress Disorder Chronification via Monoaminooxidase and Cortisol Metabolism

“…Moreover, an activation of MAO-A expression in neurons via higher ability to receptor binding was described for glucocorticoids [10]. Interestingly, low levels of basal corticosterone [16] and low levels of cerebral MAO without distinguishing the isoforms of MAO linked to physical activity were shown in rats, three days after traumatic stress [17]. And, in more physical active offensive rats we found a reduction of anxiety, corticosteroids and glutamate as well as higher concentrations of lactate in the amygdala region compared to the hippocampal region by using our model of chronic and extensive predator stress, indicating a limbic triggered HPA activity with different oxidative processes [18].…”