V. K. Akulova

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.

Changed activity of the hypothalamic-pituitary-adrenocortical system in prenatally stressed female rat during aging.

We studied the effects of daily 1-h immobilization of female rats on days 15–18 of pregnancy on functional activity of the hypothalamic-pituitary-adrenocortical system and its sensitivity to regulatory signals realized by the negative feedback mechanism in female progeny during aging. Prenatal stress potentiated the inhibitory processes in young animals. In aging female rats, the sensitivity of the hypothalamic-pituitary-adrenocortical system to feedback signals significantly decreased and circadian stress reactivity was disturbed. These data suggest that maternal stress modifies the age-related pattern of the hypothalamic-pituitary-adrenocortical regulation in female progeny.

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 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.

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.

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.

Features of the Action of Combined Administration of NAN-190 and Ketanserin with Low-Dose 17β-Estradiol on Depression-Like Behavior in Prenatally Stressed Rats

The aim of the present work was to compare the effects of blockade of 5-HT1A or 5-HT2A/2C serotonin receptors on depression-like behavior in adult female rats with experimental estrogen deficiency whose mothers had been subjected to prenatal stress during pregnancy. Two weeks after removal of the ovaries, ovariectomized (OE) prenatally stressed female rats received chronic administration of the 5-HT1A serotonin receptor antagonist NAN-190 (0.1 mg/kg, i.p.) or the 5-HT2A/2C serotonin receptor antagonist ketanserin (0.1 mg/kg, i.p.) alone or in combination with a low dose of 17β-estradiol (0.5 μg/rat, s.c.) for 14 days before behavior tests started and then until tests were completed. The behavioral methods used were the Porsolt test and the open field test. The results showed that chronic administration of NAN-190 to OE prenatally stressed females led to a prodepressive effect, while the combination of NAN-190 with low-dose 17β-estradiol, conversely, had an antidepressant effect in the Porsolt test. In the open field test, these two experimental groups of rats showed decreases in the amounts of grooming reactions, vertical motor activity, and exploratory activity. Administration of ketanserin to OE prenatally stressed females produced an antidepressant effect, as compared with control animals. However, combined administration of ketanserin and low-dose 17β-estradiol to OE prenatally stressed females had no positive effect on the behavior of the animals in the Porsolt test.

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.

Activity of the hypothalamic–pituitary–adrenal axis of prenatally stressed male rats in experimental model of depression

Changes in activity of the hypothalamic–pituitary–adrenal (HPA) axis were examined in adult, prenatally stressed male rats in the experimental depression model of ‘learned helplessness’. It was shown that in males descending from intact mothers a depressive-like state was accompanied by an increase in activity of the entire HPA axis. Namely, expression of corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) increased coupled to a rise in plasma levels of ACTH and corticosterone as well as in adrenal weight. At the same time, in males born to mothers who suffered stress during the last week of pregnancy a decrease was detected in activity both of the central (hypothalamus) and peripheral (adrenal cortex) parts of this regulatory hormonal axis, analogous to that we revealed previously in the ‘stress–restress’ experimental model. It is concluded that prenatal stress modifies the sensitivity of animals to inescapable intense stress impacts, as manifested in the specific pattern of HPA axis activity after stressing.

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.