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.

Characteristics of Depressive-Like Behavior of Prenatally Stressed Male Rats with Androgen Deficiency.

Characteristics of depressive-like behavior of male rats with androgen deficiency born by mothers subjected to prenatal stress during pregnancy were assessed by using Porsolt tests and open-field tests. The level of depression-like behavior in prenatally stressed males increased more intensively than in non-stressed gonadectomized males. Chronic administration of testosterone propionate (0.5 mg/kg, intramuscularly, for 14 days) increased depressive behavior in prenatally stressed gonadectomized males in contrast to its antidepressant effect in nonstressed gonadectomized rats. Prenatal stress considerably exacerbated depressive behavior of male rats under conditions of androgen deficiency and abolished the antidepressant effect of exogenously administered testosterone propionate.

[ACTIVITY OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS OF PRENATALLY STRESSED MALE RATS IN EXPERIMENTAL MODEL OF DEPRESSION].

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.

Activity of the Hypothalamic-Pituitary-Adrenal System in Prenatally Stressed Male Rats on the Experimental Model of Post-Traumatic Stress Disorder.

Using the experimental model of post-traumatic stress disorder (stress-restress paradigm), we studied the dynamics of activity of the hypothalamic-pituitary-adrenal system (HPAS) in adult male rats, whose mothers were daily subjected to restraint stress on days 15-19 of pregnancy. Prenatally stressed males that were subjected to combined stress and subsequent restress exhibited not only increased sensitivity of HPAS to negative feedback signals (manifested under restress conditions), but also enhanced stress system reactivity. These changes persisted to the 30th day after restress. Under basal conditions, the number of cells in the hypothalamic paraventricular nucleus of these animals expressing corticotropin-releasing hormone and vasopressin was shown to decrease progressively on days 1-30. By contrast, combined stress and restress in control animals were followed by an increase in the count of CRH-immunopositive cells in the magnocellular and parvocellular parts of the paraventricular nucleus and number of vasopressin-immunopositive cells in the magnocellular part of the nucleus (to the 10th day after restress). Our results indicate a peculiar level of functional activity of HPAS in prenatally stressed males in the stress-restress paradigm: decreased activity under basal conditions and enhanced reactivity during stress.

[Pecularities for action of combined administration of NAN-190 and ketanserine with low dose of 17ß-estradiol on depression-like behavior in prenatally stressed ovariectomized rats].

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 17ß-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 17ß-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 17ß-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 17ß-E2 to the prenatally stressed OVX female offspring failed to modify depressant-like behavior in the FST.

[Effects of 8-OH-DPAT and m-CPP on depression-like behavior in prenatally stressed ovariectomized rats treated with low dose of 17beta-estradiol].

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.

Development of behavioral and hormonal disorders in prenatally stressed female rats on the model of posttraumatic stress disorder.

The dynamics of changes in behavioral and hormonal manifestations of a pathological state in mature female rats born by mothers exposed to daily restraint stress on days 15-19 of pregnancy were studied in the experimental model of posttraumatic stress disorder (stress-restress paradigm). Experiments demonstrated increased anxiety in control and prenatally stressed female rats after combined stress followed by restress. This parameter remained enhanced until day 10 after restress in control rats and day 30 in prenatally stressed animals. The severity of depression increased on days 1 and 10 after restress in prenatally stressed female rats. Basal activity of the pituitary-adrenocortical axis increased only in prenatally stressed female rats under these conditions. This parameter increased 1 day after restress and decreased after day 30. It was concluded that prenatal stress could increase the predisposition to post-stress mental pathologies in experimental animals, which are manifested in increased severity and duration of behavioral and hormonal impairments.

[Modification of expression of neurohormones in hypothalamus of prenatally stressed male rats in model of posttraumatic stress disorder].

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 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.

[Distinctive features of the anxiety state development in experimental model of posttraumatic stress disorder in the prenatally stressed male rats].

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.

[Effect of prenatal stress and 17beta-estradiol on anxiety and depressive behaviors of ovariectomized female 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.

[Influence of fluoxetine and paroxetine on anxiety-like behavior in young and adult prenatally stressed male rats].

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.

[Influence of fluoxetine and paroxetine on anxiety-like behavior in young and adult prenatally stressed male rats].

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.

[The impact of early developmental impairment of the receptor-dependent glucocorticoid action on the pituitary adrenal axis activity and behavior of male rats].

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.

[Comparative efficacy of selective serotonin reuptake inhibitors in young prenatally stressed female 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.

[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.

[Influence of progesterone administration in early stage of development on morphometric parameters of the rat uterus].

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.

Effects of impaired testosterone metabolism during prenatal ontogenesis on the level of anxiety and behavior of rats in a novel environment.

The effects of administration of the aromatase inhibitor 1,4,6-androstatrien-3.17-dione (ATD) to female rats during the last third of pregnancy on the formation of behavior of offspring of both genders in a novel environment were studied. Animal behavior was assessed in the open field and elevated cross maze tests. Inhibition of testosterone aromatization during the prenatal period of development resulted in increases in anxiety and emotionality in experimental rats at age one month; increases in these measures in adult animals were seen in both males and females exposed to prenatal ATD. Intergender differences between control males and experimental females, in terms of behavioral measures in the novel environment such as motor activity, the duration of the freezing and grooming reactions, as well as well the level of anxiety, disappeared. It is concluded that impairment of testosterone metabolism during the prenatal period of development affects the formation of the behavior of rats in a novel environment as determined by genetic gender.

Characteristics of behavior and stress reactivity of the hypophyseal-adrenocortical system in rats with prenatal inhibition of testosterone metabolism.

The effects of administration of the aromatase blocker 1,4,6-androstatrien-3,17-dione (ATD) to female rats in the last third of pregnancy on the stress reactivity of the hypophyseal-adrenocortical system (HACS), behavior in a novel environment (an open field), and anxiety in an elevated cross maze in their adult offspring of both genders were studied. Inhibition of testosterone aromatization in the brain during the prenatal period of development was found to lead to a decrease in the basal activity of the HACS in males and longer-lasting hormonal stress responses in animals of both genders. However, the intergender differences in the nature of the stress reactivity of the system in the experimental animals persisted. Prenatal administration of ATD also induced increases in the levels of anxiety and emotionality and the duration of grooming reactions in males and females and eliminated intergender differences between control males and experimental females in terms of measures of behavior in a new environment such as movement activity, duration of the freezing reaction, and grooming. These data led to the conclusion that impaired testosterone metabolism in the brain during the prenatal period of development induced by administration of the aromatase blocker leads to changes in the nature of the stress response of the HACS in adult male and female rats and impairs the formation of sexual dimorphism in anxiety levels and the extent of behavioral reactions to environmental novelty in females.

[Sensitiveness to social stress in female rats with alteration of the pituitary-adrenal axis stress reactivity].

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.