Transgenerational effect of prenatal stress on behavior and lipid peroxidation in brain structures of female rats during the estral cycle.

The effect of stress in pregnant female Wistar rats on the behavior and lipid peroxidation (LP) in the neocortex, hippocampus and hypothalamus in the female F2 generation during the ovarian cycle was investigated. We subjected pregnant females to daily 1-hour immobilization stress from the 15th to the 19th days of pregnancy. Further, family groups were formed from prenatally stressed and control male and female rats of the F1 generation: group 1, the control female and male; group 2, the control female and the prenatally stressed male; group 3, the prenatally stressed female and the control male; group 4, the prenatally stressed female and male. The females of the F2 generation born from these couples were selected into four experimental groups in accordance with the family group. At the age of 3 months, behavior of rats was studied in the "open field" test in two stages of the ovarian cycle - estrus and diestrus. After 7-10 days, the rats were decapitated and the neocortex, hypothalamus and hippocampus were selected to determine the level of diene and triene conjugates, Schiff bases and the degree of lipid oxidation (Klein index). In F2 females with one prenatally stressed parent, there was no interstage difference in locomotor-exploratory activity and anxiety. If both F1 parents were prenatally stressed, female F2 rats retained interstage differences similar to the control pattern, while their locomotor-exploratory activity and time spent in the center of an "open field" decreased in absolute values. In the neocortex of F2 females in groups with prenatally stressed mothers, the level of primary LP products decreased and the level of Schiff bases increased in the estrus stage. In the hippocampus of F2 females in the groups with prenatally stressed fathers, the level of Schiff bases decreased in the estrus stage, and the level of primary LP products increased in group 2 and decreased in group 4. In the hypothalamus of F2 females in the groups with prenatally stressed mothers, the level of Schiff bases increased in the estrus stage and decreased in the diestrus; in addition, in group 3, the level of primary LP products in the estrus stage increased. Thus, we demonstrated the influence of prenatal stress of both F1 mother and F1 father on the behavior and the level of LP in the neocortex, hippocampus and hypothalamus in female rats of the F2 generation in estrus and diestrus.

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.

[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.

[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.

[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.

[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.

Effects of prenatal stress on the activity of the pituitary-ovarian system in female rats.

The comparative analysis of hormonal status was performed in mature female rats with experimental deficiency of estrogens, which mothers were exposed to stress during pregnancy. High levels of follicle-stimulating hormone and luteinizing hormone, and significantly lower amount of estradiol were observed in intact prenatally stressed females in comparison with intact non-stressed female rats. The increase in the levels of follicle-stimulating hormone and luteinizing hormone, and the decrease in estradiol concentration were more pronounced in blood serum of prenatally stressed ovariectomized rats as distinct from intact non-stressed and prenatally stressed female rats, and non-stressed ovariectomized female rats. We can conclude that prenatally stressed ovariectomized rats were characterized by an increased sensitivity to exogenous hormonal interventions and high lability of functional state of the pituitary-ovarian system.

[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.

[A comparison of a neuroprotective effects of hypoxic postconditioning and cerebrolysin in the experimental model].

Hypoxic postconditioning using episodes of mild hypobaric hypoxia is a new neuroprotective technique. We compared the neuroprotective efficacy of hypoxic postconditioning and cerebrolysin in a model of posthypoxic pathology in rats. Animals that survived the severe hypoxia (180 Torr, 3 h) were exposed to hypoxic postconditioning or received cerebrolysin. Postconditioning prevented the injury and loss of hippocampal (fields CA1, CA4) and neocortical neurons whereas cerebrolysin was protective only for CA4 and the neocortex. Besides that, postconditioning, unlike cerebrolysin, led to the complete functional rehabilitation from the severe hypoxia by normalizing the level of anxiety and the pituitary-adrenal axis activity. The findings demonstrate that the elaborated postconditioning technique might provide useful tool for therapy of posthypoxic pathology and stroke.

[Effects of the prenatal hypoxia on the hypothalamic-pituitary-adrenal axis function and working memory in rats].

A comparative analysis of the effects of severe hypobaric hypoxia in different prenatal periods on expression profiles of glucocorticoid receptors (GR) in dorsal (CA1) and ventral (dental gyrus) hippocampus and neocortex of rats, their stress reactivity and working memory has been performed in the present study for the first time. According to the data obtained, severe hypoxia in the prenatal period induces remarkable disturbances of GR expression in the neurons of neocortex of adult males but not females, that correlates to the disruption of working memory in adult males exposed to hypoxia on the prenatal 14-16th days. Elevation of stress plasma corticosterone levels have been observed only in the females subjected to hypoxia on the prenatal 17-19th days. Hypoxia in the females and males results in the differential changes in functions of hippocampus, as well as of other brain areas involved in learning.

[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.

[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.

[Analysis of 8-OH-DPAT and NAN-190 effects in young prenatally stressed rats under experimental estrogen deficiency conditions].

The present work was aimed at a comparative investigation of the effects of chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT1A receptors antagonist NAN-190 (0.1 mg/kg, i.p.) for 14 days on anxiety-like behavior in prenatally stressed female with the experimental estrogen deficiency induced by ovariectomy. Chronic administration of 8-OH-DPAT to ovariectomized prenatally stressed females resulted in an anxiolytic effect and led to correction of the impaired levels of follitropine and estradiol. Administration of NAN-190 to ovariectomized prenatally stressed females increased the level of anxiety and more profoundly destroyed a relation between the levels of gonadotropic hormones and peripheral gonadal hormones.

[The effect of dehydroepiandrosterone-sulphate on stress behavior in high- and low-anxiety rats].

We studied the effect of preliminary three-fold administration of dehydroepiandrosterone-sulphate (DHEA-S) on behavioral disturbance, induced by water-immobilization stress in high- and low-anxiety active rats. Active rats were selected from Wistar rats on the basis of T-maze testing. Active rats were then divided into the groups with high and low anxiety level after testing in elevated plus maze. We found that DHEA-S injections (3 mg/100 g, i.p.) had an anti-stress-like effect, as shown by a decrease stress corticosterone level in both groups of rats. DHEA-S also demonstrated an anxiolytic-like effects in high anxiety rats and anxiogenic-like effects in low anxiety rats. These results suggest that DHEA-S anxiolytic and anti-stress effects depend on the individual psycho-emotional status and baseline anxiety level.

[Characterization of depression-like behavior in prenatally stressed female rats during ovary cycle].

The aim of the present work was a comparative analysis of dynamics of depression-like behavior in prenatally stressed and non-prenatally stressed female rats in the key phases of the ovary cycle. It was found that non-stressed female rats demonstrated high level of depression-like behavior in proestrous phase as compared to the diestrous phase, whereas these rats showed low level of depression-like behavior in estrous phase in Porsolt's test. On the contrary, there were no significant differences in extent of depression-like behavior between prenatally stressed rats in the diestrous and proestrous, although in the phase of estrous in these animals an increase in level of depression-like behavior was noted. Thus, the results of this study indicated pronounced effects of prenatal stress on the character of depression-like behavior of females in different phases of ovary cycle. This study revealed leveling and reversed action of prenatal stress on depression-like behavior in key phases of sexual cycle in female rats.

[Behavioral effects of ketanserine in prenatally stressed female rats].

Comparative study of the effects of chronic administration of 5-HT(2A/2C)-receptors agonist (m-CPP, 0.5 mg/kg, i.p.) and 5-HT(2A/2C)-receptors antagonist (ketanserine, 0.1 mg/kg, i.p.) for 14 days on the anxiety- and depression-like behavior in adult prenatally stressed female rats showed that prenatal stress increased the anxiety level in female rats. Chronic administration of ketanserine produced anxiolytic and antidepressant effects, which inhibited the negative action of prenatal stress on the emotional behavior, whereas chronic administration of m-CPP did not change the emotional behavior.