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We report here studies of the effects of stressing male rats in the stress–restress paradigm, which is a model of post-traumatic stress disorder (PTSD), on the behavioral phenotype and the hypophyseal-adrenocortical system (HAS) in their adult offspring of both sexes. These experiments showed that only some proportion of males formed a PTSD-like state characterized by a reduced basal corticosterone level. The offspring of these rats had low body weight in the neonatal period of development and as adults were characterized by reduced movement activity and increased behavioral depressivity. Basal and stressed HAS activity in these animals was reduced and the sensitivity of this hormonal axis to negative feedback signals was increased. Behavioral changes were most marked in male offspring, while sequelae of the paternal PTSD-like state in female offspring were seen only in relation to activity levels and HAS activity. The offspring of males not forming a PTSD-like state displayed the smallest changes in behavior and HAS activity. It is suggested that the severity of the action of paternal stress on the offspring is determined by the individual stress resistance of fathers.

Prenatal stress is regarded as a risk factor for the development of diseases such as mental, cardiovascular, and metabolic disorders in later life. Dysregulation of the activity of the hypothalamo-hypophyseal-adrenocortical system (HHAS) is one of the mechanisms producing these disorders. Regulation of the HHAS is mediated by two types of receptor – mineralocorticoid (MR) and glucocorticoid receptors (GR) – in the corticolimbic structures of the brain. The link between prenatal stress, sex, and HHAS activity, as well as the role of central MR and GR in this interaction, has received insufficient study. We have investigated the effects of prenatal stress on HHAS activity in adult male and female rats and the expression of GR and MR in the hippocampus and medial prefrontal cortex (mPFC). Prenatal stress was modeled by subjecting pregnant female Wistar rats to 1-h restraint from days 15 to 19 of pregnancy. Basal HHAS activity and stress corticosterone levels in response to 30-min restraint were studied in their adult offspring. GR and MR expression was assessed by western blotting and also, in the hippocampus, by an immunohistochemical method. Prenatally stressed males displayed prolonged stress responses, while females showed increases in basal and stress reactivity, along with increases in the sensitivity of the HHAS to feedback signals. In males, changes in HHAS activity were accompanied by decreases in GR and MR content in the hippocampus and mPFC with an unaltered GR:MR ratio. Prenatally stressed females showed increased expression of GR protein and decreased quantities of MR protein in the hippocampus and an increased GR:MR ratio in both areas of the brain. The hippocampus of male and female animals showed changes in GR and MR content in field CA3 and the dentate gyrus. These data indicate that sex-dependent changes in GR and MR protein expression in the hippocampus and mPFC contribute to modifications of HHAS activity due to prenatal stress.

—We studied the capability to learn in a passive avoidance task and the rate of its extinction in male rats whose fathers were subjected to stress during the period of spermatogenesis using the “stress–restress” paradigm (a model of post-traumatic stress disorder). In the brain of trained and untrained rats, we studied the expression of genes encoding insulin-like growth factor II and H19, the expression of which is imprinted at the early stages of ontogeny. Experimental males exhibited impaired memory consolidation and accelerated extinction of a passive avoidance response. The expression of Igf2 was decreased in the hippocampus and neocortex of untrained male offspring of stressed fathers. The increased expression of the Igf2 and H19 genes was revealed in the hippocampus of male offspring of control fathers 20 h after training, whereas in the experimental rats, the expression of these genes did not alter. Our data show that the impairment of memory in male offspring of stressed fathers may be mediated by decreased expression of the Igf2 gene.

Clinical studies have shown that sympathetic hyperactivation (sympathetic overdrive) is one of the main features of arterial hypertension, type 2 diabetes, and obesity, which are often found simultaneously.The landmark British Prospective Diabetes Study (UKPDS), which lasted 20 years, showed that beta-blockers reduce any-cause mortality by 23 % in patients with young and middle-aged hypertension, overweight or obese with diabetes 2 type. The researchers concluded that the advantage of long-term use of BB in this study is due to the fact that in a population of patients with obesity, diabetes mellitus, hypertension and an extremely high level of activity of the sympathetic system of β1-blockade is especially effective.An analysis of subsequent large-scale clinical trials of the effectiveness of beta-blockers (in particular, bisoprolol in CIBIS II) showed that in patients with heart failure and diabetes, these drugs reduce overall mortality by 16 %.The safety study of the use of bisoprolol in effective therapeutic doses in patients with type 2 diabetes mellitus and hypertension did not reveal a statistically significant negative effect of this highly selective β1-blocker on carbohydrate and lipid metabolism.

—We studied the role of vascular endothelial growth factor (VEGF) in post-hypoxic damage of the rat brain and in the effect of saliphene, a GABA derivative that is considered as a potential neuroprotector. The method of quantitative immunohistochemistry was used to evaluate the expression of VEGF in the rat brain (neocortex and hippocampus) at the early and late periods after perinatal hypoxia and the subsequent administration of saliphene. Hypoxia resulted in an increase in the expression of vascular endothelial growth factor in the developing rat brain, and injections of saliphene prevented an increase in VEGF expression, leaving this index at the level of the control values. Thus, the changes the expression of vascular endothelial growth factor (VEGF) in the rat brain after perinatal hypoxia may be considered as a marker of the neuroprotective effect of saliphene.

The activity of glutathione-associated antioxidant enzymes in subcellular fractions (cytosolic, mitochondrial, and cell nucleus fractions) was investigated in the liver of adult male Wistar rats born after prenatal stress was. Two groups of animals were studied in the experiment: (1) control group included - animals was born by intact mothers, and (2) prenatal stress group included animals whose mothers were subjected to immobilization stress in high-light conditions from the 15th to the 19th day of pregnancy. The activity of glutathione peroxidase (EC 1.11.1.9) in prenatally stressed animals decreased in the fractions of nuclei and mitochondria compared to the control group, while the activity of glutathione reductase (EC 1.8.1.7.) increased in the same subcellular fractions. The activity of glutathione transferase (EC 2.5.1.18) in prenatally stressed rats reduced in the cytosol and mitochondrial fractions as compared to control group. Redistribution of the antioxidant enzyme activity in the cytosol, the fraction of nuclei and the mitochondrial fraction of liver tissue may contribute to the formation of the pathological phenotype of prenatally stressed offspring.Opredelena aktivnost' glutation-zavisimykh antioksidantnykh fermentov v subkletochnykh fraktsiiakh (tsitozol'noĭ, mitokhondrial'noĭ i iadernoĭ) pecheni vzroslykh krys samtsov linii Wistar, rodivshikhsia posle perenesennogo prenatal'nogo stressa. V éksperimente ispol'zovalos' dve gruppy zhivotnykh: (1) kontrol' — zhivotnye, rodivshiesia u intaktnykh samok, i (2) prenatal'nyĭ stress — zhivotnye, materi kotorykh podvergalis' s 15 po 19 den' beremennosti immobilizatsionnomu stressu v usloviiakh povyshennoĭ osveshchennosti. U prenatal'no stressirovannykh zhivotnykh aktivnost' glutationperoksidazy (KF 1.11.1.9) snizhaetsia vo fraktsiiakh iader i mitokhondriĭ po sravneniiu s kontrol'noĭ gruppoĭ, togda kak aktivnost' glutationreduktazy (KF 1.8.1.7.) uvelichivaetsia v étikh zhe subkletochnykh fraktsiiakh. Aktivnost' glutationtransferazy (KF 2.5.1.18) u prenatal'no stressirovannykh krys snizhaetsia v tsitozole i mitokhondrial'noĭ fraktsii po sravneniiu s kontrol'nymi zhivotnymi. Pereraspredelenie aktivnosti issledovannykh antioksidantnykh fermentov v tsitozole, iadernoĭ i mitokhondrial'noĭ fraktsiiakh tkani pecheni mozhet vnosit' vklad v formirovanie patologicheskogo fenotipa prenatal'no stressirovannykh potomkov.

The negative long-term effects of hypoxic exposure on postnatal day 2 (human incomplete pregnancy model) on behavior (open field test) and activity of the hypothalamic-pituitary-adrenal (HPA) axis were studied in pubertal rats together with the possibility of their correction by post-hypoxic administration of a GABA derivative salifen (an adduct of γ-amino-β-phenylbutyric acid and salicylic acid). It was shown that perinatal hypoxic exposure impairs the inhibitory mechanisms in the CNS as manifested in the absence of motor activity inhibition in the open field as well as in the enhanced and prolonged stress response of the HPA axis. Post-hypoxic administration of salifen (15 mg/kg) for 14 days restored efficiently the inhibitory processes except for persistently increased hormonal stress reactivity of the HPA axis. Possible mechanisms underlying the therapeutic effects of salifen are discussed.

Sensorineural hearing loss is one of the common diseases and it represents an urgent problem of otorhinolaryngology. The most complex and significant issues are acute and sudden sensorineural hearing loss. Every year, the number of patients suffering from this pathology is steadily growing. The increase in the number of cases of sensorineural hearing loss is associated with a number of socio-medical aspects of human life at the present stage – the growth of somatic and immune pathology, frequent stresses, high noise and vibration levels, regular use of headphones, environmental degradation and the influence of other adverse factors. The widespread use of audiometric research methods contributes to a more accurate diagnosis of impaired sound in patients of various age groups, which also affects the epidemiological data. In connection with the above, the study of modern treatment options for patients with sensorineural hearing loss is an urgent problem of clinical medicine.

Noninvasive fungal sinusitis is a widespread disease of the top respiratory tracts. The disease can proceed a long time asymptomatically or have a clinical demonstration with a dominance of a neurologic and ophthalmologic symptomatology. This pathology is surgical disease and successfully responds to treatment. However, unlike a noninvasive mycotic affection of maxillary sinus, when the starting mechanism of mitsetoma grow is invasion of foreign body after stomatologic manipulations, the pathogenesis of the isolated fungal sphenoiditis remains diskutabelny. By analogy, it is suggested about a drift into the sphenoidal sinus under certain conditions of foreign substance, which becomes the trigger of development of a fungal body in a sinus. Based on the analysis of clinical cases we established the reference cliniko-anatomic features, which are defining in a pathogenesis of this disease and can be taken as a basis at differential diagnostics chronic bacteriemic and noninvasive fungalc sphenoiditis. In a pathogenesis deviations of a nasal septum, hypoplasia of nasal turbinates and also considerably oversize of the ostium of a sphenoid sinus have a basic meaning.

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.

We report here our studies of the neuroendocrine mechanisms underlying the development of an anxiety-like state in female rats at different phases of the estrous cycle (blood estradiol level) in a stress–restress post-traumatic stress disorder (PTSD) model. Quantitative immunocytochemical methods were used to demonstrate an increase in corticoliberin expression in the paraventricular nucleus (PVN) of the hypothalamus in female rats 10 days after restress in all experimental groups. On post-restress day 30, the level of corticoliberin expression in the PVN of the hypothalamus decreased to the level seen in the control group. A significant increase in vasopressin immunoreactivity during development of the anxiety-like state was seen only in the PVN of the hypothalamus in female rats in the estrus phase (low estradiol level) at the moment of severe combined stress in the stress–restress model. Thus, the most significant changes in the neuroendocrine system of the hypothalamus was seen in female rats subjected to stress in the estrus phase, this consisting of a sharp decrease in the endogenous plasma estradiol level. Hyperactivity of the hypothalamic component of the vasopressinergic system can evidently be regarded as one of the mechanisms forming the experimental anxious PTSD-like state in female rats in the stress–restress model.

Previous studies indicated that reduced androgen levels may contribute to both physical and cognitive disorders in men, including Alzheimer's disease. New drug candidates for Alzheimer's disease in patients with androgen deficiency should ideally be able to act not only on multiple brain targets but also to correct impaired endocrine functions in hypogonadal men with Alzheimer's disease. Ropren® is one such candidate for the treatment of Alzheimer's disease in men with an imbalance of androgens. Accordingly, the aim of the current study was to examine the effects of long-term Ropren® administration (8.6mg/kg, orally, once daily, for 28 days) on the anxiety-like behavior and monoamines levels in the rat hippocampus using a β-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. Ropren® was administered to the gonadectomized (GDX) rats and GDX rats treated with testosterone propionate (TP, 0.5mg/kg, subcutaneous, once daily, for 28 days). Anxiety-like behavior was assessed in the elevated plus maze (EPM) and the light-dark test (LDT), locomotor and grooming activities were assessed in the open field test (OFT). Ropren® alone or in combination with TP-induced anxiolytic effects as evidenced in the EPM and in the LDT and increased locomotor activity in the OFT. Additionally, it was observed that dopamine (DA) and serotonin (5-HT) levels increased while 5-hydroxyindoleacetic acid (5-HIAA)/5-HT ratio in the hippocampus decreased. Our results indicate that Ropren® has a marked anxiolytic-like action due to an increase in the monoamines levels in the experimental rat model of Alzheimer's disease with altered levels of androgens.

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.

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.

The present preclinical study was designed to examine the effects of prolonged Ropren® administration (8.6 mg/kg, orally, once daily, 28 days) in a β-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. The experimental model was created by intracerebroventricular injection of β-amyloid (25-35) into gonadectomized (GDX) rats and GDX rats with testosterone propionate (TP, 0.5mg/kg, subcutaneous, once daily, 28 days) supplementation. Ropren® was administered to the GDX rats and GDX rats treated with TP. Memory performance was assessed using the passive avoidance and the Morris water maze tests and the spontaneous locomotor activity was assessed using the open field test. Treatment with Ropren® significantly improved and restored the cognitive ability of GDX rats with β-amyloid (25-35)-induced amnesia in the passive avoidance test and Morris water maze. Co-administration of Ropren® with TP exerted a markedly synergistic memory-enhancing effect in the GDX rats with β-amyloid (25-35)-induced amnesia on the same models of memory testing. Ropren® administered alone or together with TP significantly enhanced crossing, frequency of rearing and grooming of the GDX rats with β-amyloid (25-35)-induced amnesia in the open field test. These results indicate that Ropren® has a marked memory-enhancing action in the experimental model of Alzheimer's disease in male rats with altered levels of androgens.

Mucocele of the paranasal sinuses is a rare disease not infrequently associated with massive bone destruction, orbital and intracranial complications. The authors report a patient presenting with the giant post-traumatic frontal mucopyocele associated with the erosion of the posterior and inferior sinus walls that was clinically manifested as hypo- and exophthalmos and has caused the inferolateral eye deviation and orbital decompression. The patient displayed the ophtalmological symptoms 8 years after the frontal sinus fracture. The mucopyocele was treated effectively with the combination of the endoscopic trans-ethmoidal and open trans-frontal approaches. The noticeable intraoperative finding in this patient was the absence of complaints as well as the combination of dura mater defects in the form of its erosion and the leakage of the cerebrospinal fluid together with the presence of purulent discharge in the sinus in the absence of intracranial complications.Мукоцеле околоносовых пазух - редко встречающаяся патология, которая может приводить к массивным разрушениям, орбитальным и внутричерепным осложнениям. Нами представлено клиническое наблюдение посттравматического мукопиоцеле лобной пазухи с разрушением задней и нижней стенок, клинически проявляющееся выраженным гипо- и энофтальмом. В представленном наблюдении описана успешно примененная хирургическая методика трансэтмоидальной и трансфронтальной декомпрессии орбиты. Особенностью данного случая является длительное отсутствие жалоб, а также интраоперационно обнаруженное сочетание дефекта твердой мозговой оболочки и гнойного содержимого в пазухе.

This study elucidated the potential antidepressant-like effect of prolonged Ropren® administration (8.6 mg/kg, orally, once daily for 28 days) using a β-amyloid (25-35) rat model of Alzheimer's disease following gonadectomy. The experimental model was created by intracerebroventricular injection of β-amyloid (25-35) into gonadectomized (GDX) rats and GDX rats with testosterone propionate (TP, 0.5 mg/kg, subcutaneous, once daily, 28 days) supplementation. Ropren® was administered to the GDX rats and GDX rats treated with TP. Depression-like behavior was assessed in the forced swimming test, and the spontaneous locomotor activity was assessed using the open-field test. The corticosterone and testosterone levels in the blood serum before and after FST were measured in all experimental groups. Treatment with Ropren® significantly decreased the immobility time of GDX rats with β-amyloid (25-35) in the forced swimming test. Coadministration of Ropren® with TP exerted a markedly synergistic antidepressant-like effect in the GDX rats with β-amyloid (25-35 on the same model of depression-like behavior testing. Ropren® administered alone or together with TP significantly enhanced crossing, frequency of rearing, and grooming of the GDX rats with β-amyloid (25-35) in the open-field test. Moreover, Ropren® administered alone or together with TP significantly decreased the elevated corticosterone levels in the blood serum of GDX rats with β-amyloid (25-35) following the forced swimming test. These results indicate that Ropren® has a marked antidepressant-like effect in the experimental model of Alzheimer's disease in male rats with altered levels of androgens.

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.

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 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.

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 the manifestation of the pathological state in the paradigm “stress-restress” consists in hyperactivation of the hypothalamic chain of regulation of the hypothalamus-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 characteristics of the formation of a pathological state in an experimental model of post-traumatic stress disorder (PTSD) in adult female rats born to mothers subjected to daily restraint stress during the last third of pregnancy were studied. Both control and prenatally stressed female rats developed a pathological state after severe combined stress and subsequent restress, with long-lasting increases in anxiety and enhanced fast feedback inhibition of stress-related hypophyseal-adrenocortical system (HAS) activity. However, while development of the pathological state in control animals progressed to the anxiety type, prenatally stressed animals developed not only anxiety, but also increased depression-like behavior, i.e., an anxiety-depression disorder developed. These data are interpreted in the light of the interaction between the characteristics of HAS activity in prenatally stressed females and the predisposition of these animals to developing poststress pathology.

Using the immunohistochemical method, we studied the expression of glucocorticoid receptors (GRs) in the hippocampus during the postnatal period of development of male rats that were born to dams that were subjected to immobilization stress from the 15th to 19th day of pregnancy. In addition, we used Western blotting to study changes in the expression of the transcription factor NGFI-A in the hippocampus of prenatally stressed animals. We found that prenatal stress induces a considerable decrease in the number of GR-positive cells in the CA1 area of the hippocampus and dentate gyrus during the 1st week of life, an increase in their number and the number of strongly immunopositive cells during the 2nd week, and a decrease in the number of GR-expressing cells in the 3rd week of life. The expression of NGFI-A in the hip-pocampus of prenatally stressed males increased during the 1st and 2nd weeks of life but did not change during the 3rd week as compared to the control animals. We conclude that the destructive effects of prenatal stress on the developing hippocampus may be determined by alteration of the number of GRs in the early postnatal period, whereas induction of NGFI-A in the hippocampus of prenatally stressed males in the early neonatal period possibly has an adaptive character.

We compared the effects of an antagonist of 5-HT1A receptors, NAN-190 (0.1 mg/kg intraperitoneally), and an antagonist of 5-HT2A/2C receptors, ketanserin (0.1 mg/kg intraperitoneally), which were chronically injected for 14 days, on the anxiety level in prenatally stressed female rats with an ovariectomyinduced experimental deficiency of estrogens. Chronic administration of ketanserin to ovariectomized prenatally stressed females had an anxiolytic effect and corrected disturbed levels of follitropin, lutropin, and estradiol. Administration of NAN-190 to ovariectomized prenatally stressed rats increased the anxiety level and decreased the ratio between the levels of tropic and peripheral sex hormones.

The effects of dehydroepiandrosterone sulfate (DHEA-S) on changes in the levels of anxiety induced by administration of the stress neurohormone corticoliberin were studied. A T maze was used to select Wistar rats with active and passive strategies of adaptive behavior. Testing of the active group in an elevated plus maze was used to select low- and high-anxiety individuals. Intranasal administration of corticoliberin to low-anxiety active rats resulted in decreases in total activity and increases in the level of anxiety, while high-anxiety animals had low sensitivity to this neurohormone. Prior administration of DHEA-S at a dose of 3 mg/100 g had antistress effects in low-anxiety rats and anxiolytic effects in high-anxiety rats. In passive animals, which were characterized by initially high levels of anxiety and were resistant to corticoliberin, administration of DHEA-S also had antistress actions. These results led to the conclusion that the effects of DHEA-S depended on the initial psychoemotional state and behavioral sensitivity to corticoliberin.

The experiments reported here addressed comparative analysis of the role of 5-HT1A serotonin receptors in the mechanisms mediating cognitive processes during natural cyclical changes in sex hormone levels in adult female rats. The effects of chronic (14 days) administration of the 5-HT1A serotonin receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and the 5-HT1A serotonin receptor antagonist NAN-190 (0.1 mg/kg, i.p.) to females at different phases of the ovarian cycle on conditioned reflex responses were studied. A conditioned passive avoidance reaction and the Morris water maze were used as behavioral tests. Chronic administration of NAN-190 to females led to the appearance of the conditioned passive avoidance response in the proestrus and estrus phases, in contrast to control females, but had no effects on the dynamics of spatial learning in the Morris water test. Chronic administration of 8-OH-DPAT consistently impaired the processes of non-spatial and spatial learning in females regardless of the phase of the ovarian cycle. The results obtained in these experiments evidenced the modulatory role of 5-HT1A serotonin receptors in learning processes in rats in key phases of the ovarian cycle.

We studied the effects of immobilization of female rat during days 15–18 of pregnancy on the behavior in novel environment (open field test) and blood level of steroid hormones in their female offspring depending on the cycle phase and age. The rats were tested at the age of 3, 12, and 24 months. Locomotor and exploratory activity and anxiety of control rats depended on the phase of estrous cycle. Age-related changes in the studied parameters were noted: locomotor and exploratory activity decreased and anxiety increased against the background of reduced secretion of the main ovarian hormones with age. In addition, blood estradiol level and behavior in novel environment virtually did not depend on age and estrous cycle phase in prenatally stressed females. Our fi ndings suggest that maternal stress has a modulatory effect on relationship between behavioral type and estrous cycle stage, as well as on age-related pattern of behavioral reactions.

The effects of treatment of rats with hydrocortisone (1 mg/100 g) or the glucocorticoid receptor blocker RU38486 (1 mg/100 g) from day 1 to day 5 of life on changes in the dynamics of the stress response of the hypophyseal-adrenocortical system (HAS), orientational-investigative activity, and anxiety in immature and adult male rats were studied. Excess glucocorticoid hormones during the early neonatal period was found to increase orientational-investigative activity and the level of anxiety in immature males without altering the functional activity of the HAS or behavior in adult rats. Conversely, impairment of glucocorticoid receptor mechanisms in brain structures in neonatal rats led to decreased feedback efficiency in the regulation of the HAS, decreases in motor activity, and increases in anxiety levels in conditions of contextual novelty, which was most clearly apparent at adult age. It is suggested that rearrangement of glucocorticoid reception during the neonatal period of development is among the causes of the various hormonal and behavioral impairments in adult individuals.

We studied effects of the selective inhibitors of serotonin reuptake fluoxetine and paroxetine, which were orally administered at a dose of 5.0 mg/kg from the 1st to 14th days of postnatal life, on the anxiety behavior and hormonal stress reactivity of mature prenatally stressed male rats. We found that prenatal stress decreased the anxiety level in mature male rats. Chronic treatment with paroxetine did not the alter the anxiety behavior of prenatally stressed males. In contrast, treatment with fluoxetine had an anxiogenic effect on their behavior, canceling the effect of prenatal stress on the anxiety behavior of male rats. Prenatal stress considerably affected the dynamics of the stress response of the pituitary-adrenal system, which was seen as disturbances in the regulation of system feedback under conditions of stress-induced activation. Chronic administration of paroxetine or fluoxetine corrected the dynamics of stress-induced levels of corticosterone in the blood of prenatally stressed males.

The effects of immobilization (1 h/day) of female rats from days 15 to 18 of pregnancy on the secretion of sex steroid hormones depending on the stage of the estrous cycle, functional activity of the hypophyseal-adrenocortical system (HAS), and its sensitivity to regulatory signals were studied in their female offspring at different stages of ontogeny. Prenatal stress was found to lead to significant impairments to the activity of the sexual system depending on the animals’ age. Older females showed a significant decrease in HAS sensitivity to feedback signals. These data provide evidence that maternal stress has a modifying effect on changes in the reproductive functions of female rats with age and on the significant decrease in the efficacy of the feedback functions of the HAS.

In this study, we performed a comparative analysis of the effects of chronic administration of an agonist of 5-HT1A receptors, 8-OH-DPAT, (0.05 mg/kg, subcutaneously) and an antagonist of 5-HT1A receptors, NAN-190, (0.1 mg/kg, intraperitoneally) for 14 days on the anxiety behavior, monoamine metabolism in the hippocampus and amygdala, and the level of sex hormones in the blood of adult female rats during the estrus cycle. Anxiety behavior was tested in an elevated X-maze. The level of monoamines and their metabolites was evaluated using HPLC with an electrochemical detector; the content of sex hormones in the blood was measured using an enzyme immunoassay. We found that chronic administration of 8-OH-DPAT has an anxiolytic effect in rats in estrus and proestrus. After treatment with NAN-190, we found clear modulation of anxiety behavior that depended on the phase of the estrus cycle, an anxiolytic effect at a high level of endogenous estrogens and an anxiogenic effect at a low level of estrogens. The anxiolytic effect of 8-OH-DPAT in female rats was accompanied by its suppressive influence on the pituitary-ovarian and noradrenergic systems and by its activating effect on the dopaminergic system of the brain. In contrast, the behavioral effects of NAN-190 in female rats during key phases of the estrus cycle corresponded to its stimulating effect of the pituitary-ovarian system and the absence of any effect on the monoaminergic systems of the brain. These data suggest that the mechanisms of anxiety include tight interaction between the ovarian hormonal system and the serotonergic brain system.

We report here studies on the delayed effects of exogenous progesterone on the formation of anxiety in female mice. Ovariectomized female mice were given seven days of replacement therapy either with the two main ovarian hormones-progesterone and estradiol benzoate-or with progesterone only; levels of anxiety were measured six hours later in the elevated plus-maze. The role of nuclear progesterone receptors in controlling the level of anxiety was assessed by giving some mice injections of the synthetic progesterone receptor blocker mifepristone 2 h before the last dose of hormones. An immunohistochemical method was used to study changes in the number of nuclear progesterone receptors in different areas of the brains of experimental animals. These studies showed that progesterone has a delayed enhancing effect on anxiety in female mice. The role of nuclear progesterone receptors in forming this behavioral characteristic was supported by a strong correlation between changes in the numbers of progesterone receptor-immunopositive cells in several brain structures and the level of anxiety. Prior blockade of progesterone receptors using mifepristone led to a maximal reduction in the level of anxiety, which was also evidence for a role for the genomic mechanisms of action of progesterone in controlling anxiety in females.

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.

The effects of preconditioning using mild repetitive hypobaric hypoxia (360 Torr for 2 h each of 3 days) have been studied in the learned helplessness model of depression in rats. Male Wistar rats displayed persistent depressive symptoms (depressive-like behaviour in open field, increased anxiety levels in elevated plus maze, ahedonia, elevated plasma glucocorticoids and impaired dexamethasone test) following the exposure to unpredictable and inescapable footshock in the learned helplessness paradigm. Antidepressant treatment (ludiomil, 5 mg/kg i.p.) augmented the development of the depressive state. The hypoxic preconditioning had a clear antidepressive action returning the behavioural and hormonal parameters to the control values and was equally effective in terms of our study as the antidepressant. The findings suggest hypoxic preconditioning as an effective tool for the prophylaxis of post-stress affective pathologies in humans.

The effects of daily immobilization stress applied to female rats on days 15 to 18 of pregnancy on the activity of the enzyme 5 alpha-reductase (isoform I), involved in the synthesis of brain neurosteroids were studied in male offspring. The results demonstrated a decrease in enzyme activity in the cerebral cortex and hypothalamus of male fetuses one day after the last session of stress, while enzyme activity was elevated in the cortex of neonates. Increases in 5 alpha-reductase activity in the cortex, hippocampus, and hypothalamus were also seen in prenatally stressed males on day 5 of life. There were reductions in plasma testosterone and progesterone levels in experimental animals on day 19 of embryonic life and in neonatal rats, the blood progesterone level in prenatally stressed rats remaining decreased at age five days. The possible involvement of neurosteroids in the actions of prenatal stress on sexual differentiation of the brain is discussed.

This report presents studies of the effects of immobilization stress applied to pregnant female rats during the last third of pregnancy on anxiety levels and neurosteroid synthesis in brain structures of adult offspring. Neurosteroid synthesis was assessed in terms of changes in the activity of 5α-reductase, the enzyme which converts progesterone into active metabolites. Prenatal stress results in a significant decrease in the level of anxiety and an increase in movement activity among adult males. Stressed rats showed increases in progesterone-5α-reductase activity in the hypothalamus, hippocampus, and frontal cortex. These results provide evidence that changes in the behavior of adult male rats due to stress in the prenatal period of development may be due to the formation of active progesterone metabolites in the brain.

Two distinct periods of sensitivity to elevated glucocorticoid hormone levels during postnatal development of the pituitary-adrenal axis were studied. Wistar rats were injected subcutaneously (s.c.) with cortisol (1 mg/kg) on postnatal days 1–5 or 14–18. The steroid treatment during the first postnatal week resulted in a decrease of the morning basal and stress-induced plasma corticosterone levels in 30 day-old male rats, as well as in rats that were injected with cortisol on the third postnatal week. Stress-induced corticosterone levels in 90-day old cortisol-treated rats were determined in blood samples drawn from the tail vein before the restraint stress, immediately after the 20-min long stress, then 60 and 180 min afterwards. Only the rats treated with cortisol during the third week showed a prolonged stress-induced corticosterone secretion, with the highest corticosterone level in 180 min after the restraint stress. The early neonatal cortisol treatment had no effect on 3H-corticosterone binding in all studied brain areas of the 90-day old rats. The rats treated with cortisol at the 14–17th postnatal days showed a significantly lower 3H-corticosterone binding in the frontal cortex, hippocampus, and hypothalamus. These findings suggest that the third week of life in rats is more sensitive to elevated levels of corticosterone than the first one. The high level of glucocorticoids at this period has long-term effects on the efficiency of the negative feedback mechanisms provided by hypothalamus-pituitary-adrenal axis.

The stress-reactivity of the pituitary-adrenocortical system (PAS) as assessed by the dynamics of the blood corticosterone level changes was studied in rats administered with cortisol at different periods of their pre- and postnatal ontogenesis. The participation of the activation and deactivation mechanisms in this process was estimated by means of a mathematical modeling, using the basic parameters of hormonal wave. It is established that in the one-month old rat pups born from mothers injected with cortisol from the day 14 to 18 of pregnancy, the basal and stress-evoked PAS activity was not essentially changed, whereas the adult animals demonstrated a faster decrease of the stress-induced corticosterone level. Injection of cortisol at the early neonatal ontogenesis (1–5 day of life) decreased the basal and stress-induced corticosterone levels at the morning hours in one-month old rats, whereas in adult rats it increased the PAS stress-reactivity. Injection of cortisol in the late neonatal ontogenesis, i.e., during the period of formation of the sensory systems (opening of the ears, eyes, maximal motor activity) resulted predominantly in changing the time of completion of the stress-induced hormonal response that became longer than in control animals of the same age. With the aid of mathematical modeling, we have found that at the early neonatal period of development the hormonal exposure mainly increases the rate of PAS activation, whereas injection of glucocorticoids at the late neonatal period changes PAS regulation by a feedback mechanism, thus decreasing the rate of system inactivation and increasing the time of completion of PAS stress-induced reaction. It is concluded that the phenotypic reorganization of PAS stress-reactivity by exogenous corticosteroids depends on the time of their action on development of the excitatory and inhibitory mechanisms during the critical periods of their formation.

We studied the effect of chronic administration of 5-HT(1A)-receptor agonist 8-OH-DPAT (0.05 mg/kg subcutaneously) or antagonist NAN-190 (0.1 mg/kg intraperitoneally) for 14 days on anxious-depressive-like behavior of female rats during the key phases of the estrous cycle. Chronic administration of NAN-190 during the estrus phase produced an anxiogenic effect, while its administration during proestrus phase induced an anxiolytic effect. Administration of 8-OH-DPAT had no effect on anxiety level, but produced a pronounced antidepressive effect irrespective of the phase of the estrous cycle.

The effects of controllable and uncontrollable stress on the receptor binding of dexamethasone in the hypophysis and hippocampus were studied in KHA and KLA rats, lines selected for the ability to development of active escape. Presentation of the controllable stimulus led to a significant reduction in receptor binding of dexamethasone in the hippocampus with significant changes in the plasma corticosterone concentration and receptor binding in the hypophysis. KLA rats were sensitive both to the controllable and the uncontrollable stresses, with increases in plasma corticosterone and receptor binding of dexamethasone in the hypophysis. It is concluded that receptor binding of dexamethasone in the hippocampus and hypophysis depend not only on the behavioral strategy of the animal, but also on the possibility of controlling the situation.

The aim of the present study was to explore the mood effects of D1 receptor agonist, SKF-38393 and D1 receptor antagonist, SCH-23390 alone or in combination with a low dose of 17β-estradiol (17β-E2) in the adult ovariectomized female rats (OVX). OVX rats of Wistar strain were used in all experiments. Two weeks after surgery rats were chronically treated with vehicle, a low dose of 17β-E2 (5.0 μg/rat), SKF-38393 (0.1 mg/kg), SCH-23390 (0.1 mg/kg), SKF-38393 plus 17β-E2 or SCH-23390 plus 17β-E2 for 14 days before the forced swimming test. We found that SCH-23390 significantly decreased immobility time in the OVX females. A combination of SCH-23390 with a low dose of 17β-E2 induced more profound decrease of immobility time in the OVX rats compared to the rats treated with SCH-23390 alone. On the contrary, SKF-38393 failed to modify depression-like behavior in the OVX rats. In addition, SKF-38393 significantly blocked the antidepressant-like effect of 17β-E2 in OVX rats. Thus, the D1 receptor antagonist SCH-23390 alone or in combination with a low dose of 17β-E2 exerted antidepressant-like effect in OVX female rats, while the D1 receptor agonist SKF-38393 produced depressant-like profile on OVX rats.

We studied the effects of chronic administration (14 days) of agonist of 5-HT2B/2C serotonin receptors m-CPP (0.5 mg/kg subcutaneously) and agonist of 5-HT2A/2C serotonin receptors ketanserin (0.1 mg/kg intraperitoneally) on conditioned reactions in female rats in different phases of the estrous cycle. Passive avoidance (PA) paradigm and Morris water maze were used as behavioral tests. Chronic administration of m-CPP did not affect PA retrieval during the proestrus and estrus phases, but improved the dynamics of spatial learning in Morris water maze in comparison with control rats. Chronic administration of ketanserin uniformly impaired processes of spatial and nonspatial learning in female rats irrespective to the phase of the estrous cycle. A modulating role of 5-HT2A/2C and 5-HT2B/2C serotonin receptors in process of learning in female rats during the key phases of the estrous cycle was demonstrated.

Corticosteroid hormones are important intrinsic factors that not only mediate the response to stress but also largely contribute to the main physiological processes. The biological actions of these steroids involve, first of all, the activation of specific receptors, namely mineralocorticoid (MR) and glucocorticoid (GR) receptors. These two receptor types govern a flexible and well-balanced mechanism that leads to the often opposing changes in the cell. The hippocampus is the central part of the extrahypothalamic feedback loop in the control of the hypothalamic-pituitary-adrenal (HPA) axis activity. The coexpression of both MR and GR in the hippocampus serves a coordinated response to corticosteroids in the hippocampal neurons, thereby mediating the neuronal excitability, stress response, and behavioral adaptation. Each receptor type reveals distinct ontogenetic pattern over the postnatal period. This review addresses the issues relating to postnatal development of the HPA axis and especially the hippocampal expression of the GR proteins in intact and prenatally stressed rats.

Expression of glucocorticoid receptor protein in the hippocampus and frontal cortex of male and female rats during the 1st, 2nd, and 3rd weeks of life was studied by Western blot hybridization. In the frontal cortex, the concentration of receptor protein progressively increased from the 1st to the 3rd week of life; in females, expression of 94-kDa protein significantly surpassed that in males during the 1st week of life. In the hippocampus, expression of 94-kDa and 82-kDa proteins during the 1st week of life was higher in males. Moreover, expression of the major glucocorticoid receptor isoform (94 kDa) in this structure remained unchanged in all periods of the study in males, whereas in females it was low over the first 2 weeks of life and increased by the 3rd week. Variations in the expression of glucocorticoid receptors in the hippocampus of male and female rats coincide with changes in plasma corticosterone concentration during the early postnatal ontogeny.

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.

The preconditioning (PC) by using mild intermittent hypobaric hypoxia (PC) increases a resistance of the brain to severe hypoxia/ischemia and various stresses. Recently, potent antidepressant-like effects of PC have been described in animal models of depression. In the present study, the impact of PC on the activity and feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA) impaired in depression has been studied in the model of shock-induced depression in rats. PC completely prevented depressive-like behavior (54% reduction in ambulance, 59% reduction in rearing in the open field, 654% increase of the anxiety level in the elevated plus maze), the HPA hyperactivity and the impairment of HPA feedback regulation that appeared in response to the inescapable footshock. Not affecting basal HPA activity, PC remarkably enhanced the HPA reactivity to stresses and substantially up-regulated the expression of glucocorticoid receptors in the ventral hippocampus following footshock that apparently contributes to the mechanisms responsible for the antidepressant-like action of PC.

An enhancement of stress reactivity of the hypophysial-adrenocortical system in response to emotional and physical influence was shown in rats with a low threshold of sensitivity to electrical current. This phenomenon was observed as a rise in the maximum level of blood corticosterone and acceleration of stressor hormonal response. In the high-threshold rats a decrease in sensitivity of the hypophysial adrenocortical system to the feedback signals was observed.

Circulating glucocorticoids, of which their concentration is largely under the control of the hypothalamic-pituitary adrenal (HPA) axis, acting through the glucocorticoid receptors (GR) regulate a large variety of pivotal functions of the organism such as growth, development, immune- and stress-response. The main mechanism of regulation of the HPA axis activity is via negative feedback at all levels of the HPA axis itself as well as at the extra-hypothalamic level, a central part of which is the hippocampus. During neonatal development, the HPA axis of rats undergoes a period of hyporesponsiveness (SHRP)-when most stress stimuli fail to induce stress-response. Here, we describe the pattern of GR proteins expression in the hippocampal area of the rat brain during postnatal development and in adulthood. We demonstrated that the GR protein, of which its expression level is gradually enhanced in the hippocampus during postnatal life, exists in three different molecular sized forms. A larger molecular form was expressed at rather high levels at all studied time periods. A second smaller variant of GR was transiently expressed during the first one and a half weeks that corresponds with SHRP and then appeared again only in the adulthood. By the end of SHRP on PD 13, third smallest protein form of GR started to be detected in the hippocampal area. Thus, it remains to be disclosed in the nearest future, how the hippocampal GR isoforms may be involved in regulation of the neonatal HPA axis hyporesponsiveness as well as in functions of this system during the ensuing period of the brain maturation.

Studies on rats with experimental diabetes induced by administration of alloxan showed that transcranial electrostimulation of endorphinergic brain structures stimulates the regeneration of damaged beta-cells in pancreatic islets of Langerhans. This was identified on pancreatic sections stained with hematoxylin and eosin. De novo formation of small islets was noted, as evidenced by their regeneration from progenitor cells. After transcranial electrostimulation, islet beta-cells stained by the Gomori method showed recovery of granularity - a sign of insulin production. Application of an immunoenzyme method demonstrated recovery of blood insulin levels, the dynamics of increases in which showed a highly significant negative correlation with a decrease in blood glucose. These data led to the conclusion that the antihyperglycemic effect of transcranial electrostimulation in experimental alloxan diabetes results from reparative regeneration of beta-cells in islets of Langerhans with recovery of their insulin-producing function.