V. I. Mironova

Antidepressant-like effects of mild hypoxia preconditioning in the learned helplessness model in rats.

The effects of preconditioning using mild repetitive hypobaric hypoxia (360 Torr for 2 h each of 3 days) have been studied in the learned helplessness model of depression in rats. Male Wistar rats displayed persistent depressive symptoms (depressive-like behaviour in open field, increased anxiety levels in elevated plus maze, ahedonia, elevated plasma glucocorticoids and impaired dexamethasone test) following the exposure to unpredictable and inescapable footshock in the learned helplessness paradigm. Antidepressant treatment (ludiomil, 5 mg/kg i.p.) augmented the development of the depressive state. The hypoxic preconditioning had a clear antidepressive action returning the behavioural and hormonal parameters to the control values and was equally effective in terms of our study as the antidepressant. The findings suggest hypoxic preconditioning as an effective tool for the prophylaxis of post-stress affective pathologies in humans.

Involvement of the hypothalamic-pituitary-adrenal axis in the antidepressant-like effects of mild hypoxic preconditioning in rats

The preconditioning (PC) by using mild intermittent hypobaric hypoxia (PC) increases a resistance of the brain to severe hypoxia/ischemia and various stresses. Recently, potent antidepressant-like effects of PC have been described in animal models of depression. In the present study, the impact of PC on the activity and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA) impaired in depression has been studied in the model of shock-induced depression in rats. PC completely prevented depressive-like behavior (54% reduction in ambulance, 59% reduction in rearing in the open field, 654% increase of the anxiety level in the elevated plus maze), the HPA hyperactivity and the impairment of HPA feedback regulation that appeared in response to the inescapable footshock. Not affecting basal HPA activity, PC remarkably enhanced the HPA reactivity to stresses and substantially up-regulated the expression of glucocorticoid receptors in the ventral hippocampus following footshock that apparently contributes to the mechanisms responsible for the antidepressant-like action of PC.

The possible use of hypoxic preconditioning for the prophylaxis of post-stress depressive episodes.

The protective effects of hypoxic preconditioning on the development of depressive states in rat models were studied. Three episodes of intermittent preconditioning using hypobaric hypoxia (360 mmHg, 2 h) prevented the onset of depressive behavioral reactions, hyperfunction of the hypophyseal-adrenal system, and impairments in its suppression in the dexamethasone test in rats following unavoidable aversive stress in a model of endogenous depression. The anxiolytic and antidepressant actions of hypoxic preconditioning in experiments on rats were no less marked than those of the tetracyclic antidepressant ludiomil. The results obtained here provide evidence that preconditioning with intermittent hypobaric hypoxia increases resistance to psychoemotional stresses, has marked anxiolytic and antidepressant effects, and can be used for the prophylaxis of depressive episodes.

Stable Modifications to the Expression of Neurohormones in the Rat Hypothalamus in a Model of Post-Traumatic Stress Disorder

We report studies of the neuroendocrine mechanisms of development of an anxiety state in rats using the “stress-restress” experimental model of post-traumatic stress disorder. Immunocytochemical methods demonstrated significant increases in corticoliberin expression in both the parvo- and magnocellular parts of the paraventricular nucleus persisting to 10 days after presentation of the animals with repeated stress. Decreases in vasopressin expression were seen in the paraventricular nucleus of the animals on the first day after repeated stress. Vasopressin contents in the parvocellular part of the nucleus in animals of the experimental group were no different at 10 days from those in animals of the control group, while levels in the magnocellular part were increased. These data provide evidence for the involvement of the hypothalamic component of the vasopressinergic system (along with the corticoliberinergic system) in the pathogenetic mechanisms of the analog of post-traumatic stress disorder generated in this model.

Effects of Hypoxic Preconditioning on Expression of Transcription Factor NGFI-A in the Rat Brain after Unavoidable Stress in the “Learned Helplessness” Model

We report here our immunocytochemical studies establishing that the development of a depression-like state in rats following unavoidable stress in a “learned helplessness” model is accompanied by stable activation of the expression of transcription factor NGFI-A in the dorsal hippocampus (field CA1) and the magnocellular paraventricular nucleus of the hypothalamus, along with an early wave of post-stress expression, which died down rapidly, in the ventral hippocampus (the dentate gyrus) and a long period of up to five days of high-level expression in the neocortex. In rats subjected to three sessions of preconditioning consisting of moderate hypobaric hypoxia (360 mmHg, 2 h, with intervals of 24 h), which did not form depression in these circumstances, there were significant changes in the dynamics of immunoreactive protein content in the hippocampus, with a stable increase in expression in the ventral hippocampus and only transient and delayed (by five days) expression in field CA1. In the neocortex (layer II), preconditioning eliminated the effects of stress, preventing prolongation of the first wave of NGFI-A expression to five days, while in the magnocellular hypothalamus, conversely, preconditioning stimulated a second (delayed) wave of the expression of this transcription factor. The pattern of NGFI-A expression in the hippocampus, neocortex, and hypothalamus seen in non-preconditioned rats appears to reflect the pathological reaction to aversive stress, which, rather than adaptation, produced depressive disorders. Post-stress modification of the expression of the product of the early gene NGFI-A in the brain induced by hypoxic preconditioning probably plays an important role in increased tolerance to severe psychoemotional stresses and is an important component of antidepressant mechanisms.

Characteristics of the transcription factor HIF-1α expression in the rat brain during the development of a depressive state and the antidepressive effects of hypoxic preconditioning

The dynamics of HIF-1α expression during the development of stress-related depression, as well as after hypoxic preconditioning (HP), which has an antidepressant-like effect, were studied in the hippocampus, paraventricular hypothalamic nucleus, and neocortex of rats, using an immunocytochemical method. It has been found that the factor HIF-1α is induced in neurons in response to psychoemotional stress that causes the development of experimental depression in rats in the “learned helplessness” model. The profile of the stress-induced expression of HIF-1α in the hippocampus has a two-wave character: early expression on the first day and the delayed expression 10 days after the stress. No significant change was found in the neocortex. In the hypothalamus, up-regulation of HIF-1α expression was delayed (5–10 days). After HP by a moderate repetitive hypobaric hypoxia, which prevents the development of the depressive state in rats, the post-stress expression of HIF-1α was considerably altered in the brain regions studied. In the hippocampus of HP rats, the peak of the early expression lasted for about 5 days after the stress; we observed a multifold increase in its amplitude. In contrast, the HIF-1α delayed peak was eliminated. A similar but smaller effect of HP was also observed in the hypothalamus. The data obtained indicate that delayed HIF-1α expression in the hippocampus and hypothalamus was apparently involved in the mechanisms of pathogenesis of the depressive pathology. However, strong modifications in early and late post-stress expression of HIF-1α caused by HP obviously play an important role in increasing the brain’s tolerance to severe stresses and protection against the development of stress-induced depressive pathologies.

Stress-Induced Changes in Corticoliberin and Vasopressin Expression in the Hypothalamus of Female Rats in a Model of Post-Traumatic Stress Disorder

We report here our studies of the neuroendocrine mechanisms underlying the development of an anxiety-like state in female rats at different phases of the estrous cycle (blood estradiol level) in a stress–restress post-traumatic stress disorder (PTSD) model. Quantitative immunocytochemical methods were used to demonstrate an increase in corticoliberin expression in the paraventricular nucleus (PVN) of the hypothalamus in female rats 10 days after restress in all experimental groups. On post-restress day 30, the level of corticoliberin expression in the PVN of the hypothalamus decreased to the level seen in the control group. A significant increase in vasopressin immunoreactivity during development of the anxiety-like state was seen only in the PVN of the hypothalamus in female rats in the estrus phase (low estradiol level) at the moment of severe combined stress in the stress–restress model. Thus, the most significant changes in the neuroendocrine system of the hypothalamus was seen in female rats subjected to stress in the estrus phase, this consisting of a sharp decrease in the endogenous plasma estradiol level. Hyperactivity of the hypothalamic component of the vasopressinergic system can evidently be regarded as one of the mechanisms forming the experimental anxious PTSD-like state in female rats in the stress–restress model.

Behavior Disorders Caused by Perinatal Hypoxia in Juvenile Rats and Their Correction with GABA Derivative

We studied the effects of acute normobaric hypoxia on postnatal day 2 (model of preterm pregnancy) on reflex activity and behavior of juvenile male Wistar rats and the possibility of correction of behavioral deficit by administration of GABA derivative Salifen after hypoxia. It is shown, that perinatal hypoxia impaired righting reflex and forelimb grip strength and increased motor activity in juvenile male rats. Administration of Salifen for 14 days in a dose of 15 mg/kg improved reflex activity and behavior of rats, which indicates the prospect of further study of the therapeutic efficacy of this drug on models of neonatal encephalopathy.

Activity of the Hypothalamo-Hypophyseal-Adrenocortical System in Prenatally Stressed Female Rats in a Model of Post-Traumatic Stress Disorder

Changes in the activity of the hypothalamo-hypophyseal-adrenocortical system (HHAS) were studied in adult prenatally stressed female rats in an experimental model of post-traumatic stress disorder (PTSD) in which the animals were subjected to combined treatment consisting of restraint for 2 h, swimming for 20 min, and ether stress, with subsequent restress seven days later (the stress–restress paradigm). An increase in the HHAS stress response was seen after combined stress in prenatally stressed females, apparent at the time of restress. Both control and prenatally stressed animals showed increases in the sensitivity of the hormonal axis to negative feedback signals, which supported accelerated inhibition of the HHAS after its activation by stress. Only prenatally stressed females showed a decrease in the basal corticosterone level and persistence of increased HHAS sensitivity to feedback signals one month after stress and restress. Control females were found to form the PTSD-like state after stress–restress mainly via corticotropin-releasing hormone, while vasopressin was involved in this process in prenatally stressed females.