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.

[STRESS-INDUCED PATTERNS OF THE HYPOTHALAMIC CRH AND VASOPRESSIN EXPRESSION IN FEMALE RATS IN A MODEL OF POSTTRAUMATIC STRESS DISORDER].

The neuroendocrine mechanisms underlying anxiety-like state development in cycling female rats with different plasma estradiol levels have been studied in a stress-restress paradigm, an animal model of posttraumatic stress disorder (PTSD). The effect of stress-restress on the hypothalamic expression of corticotropin-releasing hormone (CRH) and vasopressin was analyzed by quantitative immunocytochemistry. Stress-restress was found to increase CRH expression in the hypothalamic paraventricular nucleus (PVN) on the 10th post-restress day, but the level of CRH expression in the PVN restored to the basal values on the 30th post-restress day in all experimental groups. It was shown an increase in vasopressin immunoreactivity in the PVN from the 10th to the 30th post-restress days in female rats exposed to stress during the estrus phase (low plasma estradiol level). In summary, female rats with low plasma estradiol level exhibited the most significant changes in the hypothalamic neuroendocrine system following stress-restress exposure. It might be hypothesized that hyperactivity of the hypothalamic circuit of the central vasopressinergic system is one of the possible mechanisms underlying PTSD-like state development in female rats in a stress-restress paradigm.

[The hypothalamic-pituitary-adrenal axis activity in prenatal stressed female rats in the model of posttraumatic stress disorder].

The effects of immobilization stress from 15th to 19th days of gestation on hypothalamic-pituitary-adrenal (HPA) axis activity in the model of posttraumatic stress disorder (stress-restress paradigm) in adult female offspring were studied. The results showed that prenatal stressed female rats demonstrated enhanced stress reactivity and hypersensitive glucocorticoid feedback of HPA in response to the restress procedure. Moreover, decrease in basal level of corticosterone was detected only in prenatal stressed female rats. Immunocytochemical staining revealed that the effects of stress-restress procedure in control female rats were accompanied by the rise in corticotropin-releasing hormone immunoreactivity in the hypothalamic paraventricular nucleus, although over-expression of hypothalamic vasopressin was founded only in prenatal stressed rats. These data suggest that hypothalamic vasopressin was involved predominantly in posttraumatic stress disorder-like state in prenatal stressed female rats.

[A test for evaluation of pituitary-adrenal axis disregulation].

In rat models, a modification of the fast feedback paradigm for the pituitary adrenocortical system applied to detect posttraumatic stress disorder (PTSD) was developed. Both standard and modified methods were used. In contrast to the standard method (injection of exogenous cortisol), the new modification suggested measuring blood corticosterone, rather than adrenocorticotropic hormone, at the early stages of development of the stress reaction (3, 10, 30, and 60 min of the exposure to stress factors). With the suggested modification, the fast feedback phenomenon was studied in reliable rat models of PTSD (stress-restress) and depression (learned helplessness). Fast pathological inhibition of the pituitary adrenocortical system by the fast feedback mechanism was revealed only during the simulated PTSD but not in the depressive-like state, which supported the specificity and validity of the developed modification of the test. Thus, the proposed methodological modification is a valid tool for diagnostics of the PTSD-specific fast feedback inhibition of the pituitary adrenocortical system in the animal models of this psychopathology.

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.

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.

[The hypoxic preconditioning effect upon expression of the NGFI-A transcription factor in the rat brain following an unavoidable stess in the "learned helpnessness" model].

In this study, by an immunocytochemistry it is established that development of the depression after an inescapable stress in the learned helplessness model in rats is associated with stable induction of the transcription factor NGFI-A in the dorsal hippocampus (CA1 field) and in the paraventricular hypothalamic magnocellular nucleus (PVNm), as well as with rapid and transient stress-induced expression of NGFI-A in the dentate gyrus and, supported on high level till 5 days, in the neocortex. Hypoxic preconditioning using mild repetitive hypobaric hypoxia (360 Torr for 2 hrs each of 3 days) prevented development of the depressive state in rats, and considerably changed the dynamics of the NGFI-A immunoreactivity in the hippocampus: the stable increase of an expression in the dentate gyrus and only transitory and delayed (for 5 day) in the CA1 field was detected. In the neocortex (Layer II) the stress influence was levelled with preconditioning by preventing the prolongation of the first wave of expression NGFI-A untill 5 days, and in PVNm, on the contrary, was stimulated the second (delayed) wave of an expression of this transcription factor. The pattern of NGFI-A expression in the hippocampus, neocortex and hypothalamus of preconditioned rats revealed an obvious pathological response to aversive stress, which results in development of depressive frustration rather than the adaptation. Stress-induced modifications of early gene product NGFI-A expression in the brain caused by hypoxic preconditioning, possibly, play important role in tolerance to hard psychoemotional stresses and may be an important part of antidepressive mechanisms.

[The anxyolytic effect of mild hypobaric hypoxia in a model of post-traumatic stress disorder in rats].

The impact of mild hypobaric hypoxia on the development of anxiety-like state in rats in experimentally simulated human post-traumatic stress disorder was studied. Three-trial exposure to mild hypobaric hypoxia (360 mm Hg for 2 hours daily, for 3 days) in preconditioning or post-conditioning mode performed, respectively, before or after exposure to severe traumatic stress in the "stress-restress" model produced a significant anxiolytic effect on the rat open-field and plus-maze behavior. Anxiolytic effect of modem antidepressant Paxil (20 mg/kg daily, for 3 days) was weaker. This drug produced side-effects on particular behavioral characteristics in the open field. The conclusion was made on the efficacy of mild hypobaric hypoxia and the possibility of its implementation as a medication-free tool for prophylaxis and correction of post-traumatic stress disorder.

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.

[Influence of progesterone receptors deficit in early stage of development on formation of the reproduction functions of female rats].

The effects of 100 mg/kg mifepristone administration from 1 to 5 postnatal days on formation of the female reproduction functions were studied. It has been shown that neonatal blockade of progesterone receptors resulted in significant decline of morphometric parameters of the adult rat uterus, as well as disturbance sex steroids secretion and decrease density of uterus progesterone receptors in the oestrus. Neonatal administration of mifepristone did not change the rat ability to reproduction in favorable condition, but induced significant fetus resorption under the gestation pathology. These data suggest that violation of progesterone receptors mechanisms in neonatal period of life exert negative influence on the female reproduction functions in adult. We suggest, that neonatal treatment of mifepristone can been used as a model of progesterone receptors deficit in the adult rat uterus.

Permanent modification of neurohormone expression in the hypothalamus of rats on the model of learned helplessness.

Depressive state of Wistar rats in the model of learned helplessness was accompanied by a persistent increase in the expression of corticotropin-releasing factor in the hypothalamus. Vasopressin content in the hypothalamus was modified only in the early poststress period and remained unchanged at the late stage of experimental depression. Our results indicate that hypothalamic corticotropin-releasing factor (but not vasopressin) plays an important role in the development of experimental mental disorders.

[Modifications of hypothalamic neurohormone expression in animal model of post-traumatic stress disorder].

Neuroendocrine mechanisms of development of anxiety-like state in rats in experimental model of human post-traumatic stress disorder (PTSD), referred to as stress-restress paradigm, have been studied. Immunocytochemistry has revealed significant increase of CRH expression in both parvo- and magnocellular subdivisions of paraventricular nuclei up to 10th post-stress day. Significant reduction of vasopressin expression in rats' hypothalamic paravntricular nuclei has been detected on the 1st post-stress day. Vasopressin immunoreactivity in hypothalamus of stressed animals was indistinguishable from that in control group on the 10th post-stress day only in parvocellular subdivision of the paraventricular nucleus, while it was increased in magnocellular subdivision of the nucleus in experimental group compared to controls. The results imply a plausible role of hypothalamic vasopressin along with CRH on the development of PTSD.

[The feasible applications of hypoxic preconditioning for prevention of post-stress depressive episodes].

The protective effect of hypoxic preconditioning on the development of depressive states in rat experimental models has been studied. Three-trial preconditioning by repetitive hypobaric hypoxia (360 mm Hg, 2h) prevented triggering of behavioral depression, pituitary-adrenal axis hyperactivity and impairment of negative feedback in dexamethasone test in rats following inescapable aversive stress in the model of endogenous depression. Anxyolytic and antidepressant-like effect of the hypoxic preconditioning was not less than that of tetracyclic antidepressant ludiomil. The findings reveal that the preconditioning by intermittent hypobaric hypoxia increases tolerance to psychoemotional stress, possesses potent anxiolytic and antidepressant-like effects and might be applied for prevention of depressive episodes.

[The extrahypothalamic level of the hypophyseal-adrenocortical system regulation appears to be involved in development of different types of depression-like state in rats].

Possible role of extrahypothalamic corticotrophin-releasing hormone (CRH) and vasopressin-producing centers in post-stress depression development were studied. We used genetically selected strains: KHA (Koltushi High Avoidance) and KLA (Koltushi Low Avoidance) rats developing different types of depression in the "learned helplessness" paradigm: the model analogues of endogenous (KHA strain) and exogenous (KLA strain) depression. Interstrain differences of control and stress-induced CRH- and vasopressin-expression in hippocampus and neocortex in the course of depression development in KHA and KLA rats were revealed using immuno-histochemical studies. It has been shown that a significant increase of CRH- and vasopressin-immune reactivity in hippocampus and neocortex of KHA rats occurred on the 10th post-stress day. We detected also decreased CRH- and vasopressin-expression in dorsal hippocampus, and increased CRH-immune reactivity in neocortex of KLA rats in the same post-stress period. These findings imply that extrahypothalamic CRH- and vasopressin-ergic systems appear to be involved in pathogenesis mechanisms of model analogues of endogenous and exogenous depression in different ways.

Expression of vasopressin in the hypothalamus of active and passive rats with poststress depression.

No interstrain differences were revealed in vasopressin concentration in the hypothalamus of control and treated active and passive rats with poststress depression. Changes in vasopressin immunoreactivity corresponded to variations in corticotropin-releasing hormone concentration observed in this model of depression. These data suggest that vasopressin contributes to the development of this experimental psychopathology.

[Dynamics of hypothalamic CRH immune reactivity in active and passive rats in the course of development of behavioural depression]. / Soderzhanie kortikoliberina v gipotalamuse krys s razlichnoi strategiei povedeniia pri poststressornoi depressii.

A possible relation between activity of the main CRH-producing centers of hypothalamus and depressive-like behavior of animals was studied. We used genetically selected strains--KHA (Koltushi High Avoidance) and KLA (Koltushi Low Avoidance) rats, demonstrating active and passive strategy of adaptive behavior in novelty situaltions, respectively. Rats were exposed to inescapable stress to develop a "learned helplessness". We observed considerable differences between two strains of animals in CRH-expression in parvo-, magno-cellular parts of the paraventricular nucleus and in the supraoptic nucleus in the course of behavioral depression development. Significant differences between control groups were seen only in paraventricular nucleus. On the 1st post-stress day in hypothalamus of KLA rats, we detected decreased CRH immune reactivity that remained unchanged up to the 10th day. In KHA rats, there were no notable changes of CRH expression in all studied nuclei. These findings, including previous results on different dynamics of behavioral changes and different hypothalamo-pituitary-adrenocortical system activity during development of depression in KLA and KHA rats, indicate that "learned helplessness" in these two groups of animals provides the model analogues of different types of depression. Besides, these findings indicate different implication of hypothalamus CRH-system in the behavioral depression development in rats with divergent strategy of adaptive behavior.

Adaptive behavior in active and passive rats after intranasal administration of corticotrophin-releasing hormone.

Rats with high (KHA) and low (KLA) rates of acquiring active avoidance reflexes were used to study the effects of intranasal administration of corticotrophin-releasing hormone on orientational-investigative behavior in an open field and anxiety in an elevated cross maze. Administration of the neurohormone induced opposite changes in the behavior of the rats of these lines in the two tests. In KLA rats, movement and investigative activity increased, while in KHA rats these behaviors decreased. In the elevated maze, KLA rats, unlike KHA rats, showed increases in the time spent in the open arms, which was evidence for a decrease in anxiety in these animals. Thus, intranasal hormone administration completely reproduced the effects seen after administration into the striatum. It is suggested that corticotrophin-releasing hormone is an endogenous factor for the detailed and appropriate correction of adaptive behavior.

[Adaptive behavior of active and passive rats after intranasal administration of the corticotropin-releasing hormone]. / Prisposobitel'noe povedenie aktivnykh i passivnykh krys posle intranazal'nogo vvedeniia kortikotropin-rilizing gormona.

Behavioural effect of intranasal application of corticotropin-releasing hormone (CRH) was investigated in rats with high (KHA) and low (KLA) rate of learning in "open field" and plus-maze (PM) active avoidance test. The neurohormone provoked the opposed changes in behaviour of rats of this strain in both tests. The level of locomotion and exploratory activity rose in KLA rats and decreased in KHA rats. After the CRH application, the KLA rats but not KHA rats spent more time in the opened alleys of the PM than the control animals. The same behavioural changes were observed in our previous research when CRH was injected in striatum. We suppose that CRH is an endogenous factor of precise correction of the adaptive behaviour.