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We report here a study examining the effects of acute normobaric hypoxia in the early postnatal period of development (postnatal day 2) on learning ability and the expression of GABAB receptors in the neocortex (medial prefrontal cortex) of adolescent rats (postnatal days 55–60) and also addressing the possibility of correcting identified disorders with the Russian-made drug salifen, a GABA derivative. Perinatal hypoxia has been shown to impair the formation and retention of memory traces in the novel object recognition and conditioned passive avoidance reflex tests and to reduce spatial learning ability in the Morris water maze test. Analysis of Western blot results revealed an increase in the quantity of GABAB receptor protein in the medial prefrontal area of the neocortex of rats exposed to perinatal hypoxia. Administration of salifen 15 mg/kg for 14 days after exposure to hypoxia improved the cognitive abilities of rats and normalized the level of GABAB receptor protein expression in the medial prefrontal cortex of rats. The results obtained here are of interest for solving an applied challenge in neonatology – the search for effective pharmacological correction of the sequelae of perinatal hypoxia. [ABSTRACT FROM AUTHOR]

The hypothalamic-pituitary-adrenal (HPA) axis activity changes were examined in the adult, prenatally stressed male rats in the experimental depression model--the paradigm of "learned helplessness". It was shown that in males descending from intact mothers a depressive-like state was accompanied by an increase in HPA activity. The expression of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) increases, coupled with a rise in plasma levels of ACTH and corticosterone as well as in adrenal weight. At the same time in males born from mothers stressed during the last week of pregnancy we observed a decrease in activity of both the central (hypothalamus) and the peripheral (adrenal cortex) parts of regulation of this hormonal axis similar to that revealed for these animals in our previous study in "stress-restress" paradigm. It is concluded that prenatal stress modifies the sensitivity of animals to the inescapable intense stress impact, which manifests itself in a specific pattern of the HPA axis activity after stress load.

The aim of the present work was to perform a comparative analysis of 5-HT(1A)- and 5-HT(2A/2C)-receptors blockade effects on depression-like behavior of the adult ovariectomized (OVX) female offspring at estrogen deficiency delivered from their prenatally stressed mothers. The adult prenatally stressed OVX female offspring were chronically (during 14 days) treated by 5-HT(1A)-receptors antagonist--NAN-190 (0.1 mg/kg, s. c.) or 5-HT(2A/2C)-receptors antagonist--ketanserine (0.1 mg/kg, i. p.) alone, or in a combination with its preparartions a low dose of 17β-estradiol (5.0 μg/rat, s. c.). All drugs were administered in 2 weeks after overiectomy during 14 days before and for all period of behavioral testing procedure. The prenatally stressed QVX female offspring were tested in the forced swimming test (FST) and the open field test (OFT). Treatment with NAN-190 alone induced marked depressant-like effect, while NAN-190 administered in a combination with a low dose of 17β-estradiol resulted in an antidepressant-like effect in the FST in the prenatally stressed OVX females as compared to the control prenatally stressed female offspring. Administration ofNAN-190 plus 17β-estradiol led to decreased frequency of rearing, exploratory and grooming behavior in prenatally stressed OVX female offspring in the OFT. Treatment with ketanserine resulted in an antidepressant-like effect in prenatally stressed OVX females in the FST as compared to the control group. However, co-administration of ketanserine with a low dose of 17β-E2 to the prenatally stressed OVX female offspring failed to modify depressant-like behavior in the FST.

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.

By the method of quantitative immunohistochemistry there has been studied expression of corticotrophin-releasing hormone (CRH) and vasopressin in hypothalamic paraventricular nucleus (PVN) of prenatally stressed rats in the experimental model of the posttraumatic stress disorder--the paradigm "stress-restress". The prenatal stress was modeled by immobilization of pregnant female rats for 1 h from the 15th to the 19th day of pregnancy. It has been shown that in sexually mature males--descendants of stressed mothers--a decrease in immunoreactivity to CRH and vasopressin is observed in the parvocellular and magnocellular PVN areas 10 days after the restress. In the control group males born by intact mothers the level of immunoreactivity to CRH was increased in both PVN areas, whereas with respect to vasopressin--in the magnocellular area. Only in the prenatally stressed males there is detected a decrease in the corticosterone level in the blood plasma 10 days after the restress. It is concluded that in the control group males themanifestation of the pathological state in the paradigm "stress-restress" consists in hyperactivation of the hypothalamic chain of regulation of the hypothalamo-pituitary-adrenocortical system, whereas in the prenatally stressed animals, on the contrary, there is observed a decrease in activity both of the central (PVN) and of the peripheral (adrenal cortex) chain of this hormonal axis.

The present work was aimed at a comparative estimation of the effect of stimulation of 5-HTIA and 5-HT(2B/2C) receptors on depression-like behavior in adult ovariectomized (estrogen-deficient) female offspring from prenatally stressed (PS) mothers. PS ovariectomized female rats were treated for 14 days of with the vehicle, a low dose of 17beta-estradiol (5.0 microg/rat, s.c.), 5-HT(1A) receptor agonist 8-OH-DPAT (0.05 mg/kg), 5-HT(2B2C) receptor agonist m-CPP (0.5 mg/kg), 8-OH-DPAT plus 17beta-estradiol, or m-CPP plus 17beta-estradiol. Then, the behavior of PS ovariectomized female rats was studied in the forced swimming (Porsolt) test and the open-field test. It was established that 8-OH-DPAT administered alone or in a combination with a low dose of 17beta-estradiol produced an antidepressant-like effect in the forced swimming test as compared to the untreated control PS ovariectomized offspring. Application of these drugs in PS ovariectomized offspring led to decreased frequency of rearing, exploratory behavior, and grooming in the open field test. The m-CPP treatment also resulted in an antidepressant-like effect in PS ovariectomized offspring in the forced swimming test. However, co-administration of m-CPP with a low dose of 17beta-estradiol to PS ovariectomized offspring increased the level of depression, thus producing pro-depressant effect in the forced swimming test.

The aim of the present work was an estimation of effects of chronic administration of selective serotonin reuptake inhibitors--fluoxetine (5.0 mg/kg, p.o.) and paroxetine (5.0 mg/kg, p.o.) for 14 days of postnatal period on anxiety-like behavior in the prenatally stressed male rats during pubertal period (1,5 month) and the adult state (3 month). Chronic paroxetine administration to females failed to change an anxiety-like behavior independently from age. On the contrary, administration of fluoxetine resulted in modulating influence on the anxiety-like behavior of prenatally stressed rats dependently from age: anxiolytic effect was noted in young males, while anxiogenic effect was observed in the adult male rats.

The present study evaluated the ability of 17beta-estradiol to induce anxiolytic- and antidepressant-like action in adult ovariectomized female offspring of dams that were restrained under lights for 1 h on gestational days 15-19. There were no differences in behavioral profile of ovariectomized prenatal stressed and control female rats. Injections of 17beta-estradiol (0.5 microg/rat) in the course of two week had minimal behavioral effects in control rats, but produced a decrease of immobility in the forced swimming test and anxiety level in the elevated plus maze in prenatal stressed rats. These findings suggest that ovariectomized prenatal stressed female rats demonstrate more sensitivity to estrogen-replacement.

Anxious-depressive state was studied in experimental "stress-restress" model of posttraumatic stress disorder (PTSD) using adult rat males. Rat males were born by control females and whose mothers were under 60-minute immobilization stress since 15 until 19 days of pregnancy. Then rats were exposed to a single session of prolonged stress (restraint followed by a forced swim and exposure to ether vapors) and restressed 7 days later. 10 and 20 days after restress animals were tested in elevated plus-maze to measure anxiety and forced swim test to research depression-like behavior. In both groups there were control animal that stay intact. In addition to behavior, we studied activity of hypothalamo-pituitary-adrenal axis (basal activity and fast feedback inhibition) by analysis of plasma corticosterone concentration. We found that in control and prenatally stressed (PS) rat males in 10 days after stress have pathological state such as elevated anxiety and depressive-like behavior and inhibition of stress activity of H PA axis due to activation of fast feedback. However, in PS rats signs of disorder were deeper and longer--decreased basal plasma corticosterone and increased anxiety those saved in 20 days after restress. In conclusion, we can say that prenatal stress promotes developing of stronger behavioral and hormonal pathology in "stress-restress" paradigm.

We present the results of a comparative analysis of the effects of the chronic administration of the selective serotonin reuptake inhibitors fluoxetine (5.0 mg/kg, p.o.) and paroxetine (5.0 mg/kg, p.o.) for 14 days of the postnatal period on anxiety-like behavior in the prenatally stressed male rats as studied during pubertal period (1.5 month) and in the adult age (3 month). The chronic administration of paroxetine in male rats did not change the anxiety-like behavior in male rates of any age. On the contrary, the administration of fluoxetine modulated the anxiety-like behavior of prenatally stressed rats depending on the age: the anxiolytic effect was observed in young males, while the anxiogenic effect was observed in adult male rats.

Effects of the chronic administration of selective serotonin reuptake inhibitors (SSRIs) fluoxetine (daily 5.0 mg/kg, p.o.) and paroxetine (daily 5.0 mg/kg, p.o.) for 14 days of postnatal period on anxiety-like behavior have been studied during pubertal period in prenatally stressed female rats. It was found that prenatal stress reduced the anxiety level in test rats. Chronic administration of paroxetine in female rats did not change their anxiety-like behavior. Administration of fluoxetine resulted in an anxiogenic effect, but leveled an action of prenatal stress on the anxiety-like behavior in prenatally stressed female rats during pubertal period.

The effects of administration of cortisol or glucocorticoid receptor antagonist RU 38486 to male rats from days 1 to 5 of postnatal life on the stress reactivity of the pituitary-adrenocortical axis, open field behavior, and anxiety in an elevated-plus maze were studied. Neonatal cortisol administration induced increase in locomotor and rearing activity as well as anxiety level in 30-day-old male rats, but the pituitary-adrenocortical axis activity and behavior of adult animals was unaltered. Whereas the impairment of the receptor-dependent glucocorticoid action in neonatal brain resulted in longer-lasting hormonal stress responses, reduction number of locomotion, and increase the anxiety level in adulthood. These data suggest that changes of glucocorticoid receptors in the brain during the neonatal period of devlopment can lead to different hormonal and behavioral impairments in adult male 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.

The sensitiveness of female rats to social stress induced by increasing group density, was investigated. It was shown that female rats were housed in groups of 9-10 animala per cage in pubertal period and demonstrated significant alteration of oestrous cycle duration and anxiety level. This housing condition increased basal level of corticostcrone in prenatal stressed female rats who have high stress reactivity of the hypothalamic-pituitary-adrenal axis, as well as a more profound effect on anxiety level and oestrous cycle. Prenatal stressed rats retained impairment of oestrous cycle and behavior after optimization of housing condition, whereas control rats demonstrated normalization of oestrous cycle duration and anxiety level. These data suggest that high stress reactivity females rats are more sensitive to crowding-induced stress.

The aim of this study was to evaluate the effects of single injection of 0.5 mg progesterone in neonatal stage of development on morphometric parameters of the adult rat uterus. The results showed that there were no changes ofendometrial morphometry in respect to oestrous cycle in neonatal treated rats. Neonatal administration of progesterone decreased the myometrium thickness in oestrus and dioestrums owing to circular muscle layer, and disturbed sex steroids secretion during the oestrous cycle. These data suggest that neonatal administration progesterone reduces the endometrium sensitivity to sex steroids and produces the myometrium atrophy.

The effects of prenatal stress on the hypothalamic-pituitary-adrenal (HPA) axis activity and brain glycocorticoid receptors were studied in neonatal male and female offspring, as well as the influence of neonatal glycocorticoid receptors blockade on hormonal stress reactivity of adult rats. The results showed that there were sexual differences in plasma corticosterone level and corticosteroid binding in the cortex and hypothalamus of 5-day old control rats. Prenatal stress increased basal level of corticosterone in female rats, decreased corticosterone binding in hypothalamus and hippocampus of male and female rats, and increased corticosteroid receptor level in the male cortex. Neonatal administration of glycocorticoid receptor antagonist did not change plasma corticosterone level in 5-day old rats, but prolonged hormonal stress response of the HPA axis in adult male rats and increased hormonal stress response in female ones. The character of the IIPA axis activity of male and female rats with neonatal blockade of glycocorticoid receptors correspond to hormonal stress response of prenatal stressed rats. These data suggest that change of brain glycocorticoid receptors function in neonatal period of development might be one of the mechanisms of prenatal stress influence on the HPA axis activity in the adulthood.

The effects of maternal administration of the aromatase inhibitor 1,4,6-androstatrien-3,17-dione (ATD) during the last week of gestation on formation of behavior in a novel environment were studied in male and female offspring. The "open field" and the elevated plus-maze tests were used. The results showed that there were a significant elevation of the anxiety level and emotionality in ATD-treated 30-day-old female rats, whereas at the age of 90 days, the elevation of these behavioral parameters was observed both in males and females. There was no a sexual dimorphism in behavioral response to a novel environment such as locomotor activity, time of immobilization, total duration of grooming reaction, and anxiety level between adult control male and treated female rats. These data suggest that prenatal inhibition of the brain testosterone metabolism alters the formation of sexual dimorphism of the anxiety and behavioral response to a novel environment in adulthood.

The effects of maternal administration of the aromatase inhibitor, 1,4,6-androstatrien-3,17-dione (ATD), during the last week of gestation on stress reaction of the hypothalamic-pituitary-adrenal axis (HPA) and behavior in a novel environment (open field) and the anxiety level in the elevated plusmaze, were studied in male and female adult offspring. The results showed that parental inhibition of brain testosterone metabolism decreases the basic level of corticosterone in male rats and prolongs hormonal stress reaction of the HPA axis in both sexes. Prenatally treated rats demonstrated significant elevation of the anxiety level and emotionality. There was no sexual dimorphism in behavioral response to a novel environment such as locomotor activity, the time of immobilization, the total duration of grooming reaction, and the anxiety level, between control male and treated female rats. These data suggest a prenatal inhibition of the brain testosterone metabolism after the stress reaction of HPA axis and formation of sexual dimorphism in the anxiety and behavioral response to a novel environment in adulthood.