L. N. Maslova

Chronic stress during prepubertal development: immediate and long-lasting effects on arterial blood pressure and anxiety-related behavior.

The present work was undertaken to study the immediate and long-lasting effects of environmental stress during prepubertal life in rats with inherited stress-induced arterial hypertension (ISIAH) and normotensive Wistar rats on blood pressure (BP) levels and anxiety-related behavior. Two models of chronic stress (21-32 postnatal days) were used: repeated handling (HS) and unpredictable stress (US) of daily exposures to a variety of mild physical or psychoemotional stressors. Rats were tested just after the end of the chronic stress period and then at the age of 4 months. Chronic prepubertal stress did not affect the basal or stress-induced BP levels in young or adult Wistar rats. In ISIAH rats, chronic stress during the early phase of hypertension development did not accelerate its formation and did not augment its manifestation in adults. Moreover, the basal BP was decreased in young and adult ISIAH rats exposed to HS or US as compared to the age-matched controls. No long-lasting effect on BP elevation under acute stress in adults was found. Plasma corticosterone levels at resting and acute stress conditions were not changed in adult rats that had experienced prepubertal stress. Hypertensive rats proved to be less anxious in the elevated plus-maze test. The immediate effects of chronic stress were similar in the two rat strains: HS had an anxiolytic action while US stimulated anxiety. Long-lasting consequences depended on the rat strain: the anxiolytic effect of HS was retained in Wistar rats and US caused a greater anxiety in adult ISIAH rats. The data do not evidence that symptoms of anxiety are related to the development and maintenance of stress-sensitive arterial hypertension in ISIAH rats.

Immediate and long-lasting effects of chronic stress in the prepubertal age on the startle reflex

The immediate and long-lasting effects of two models of chronic stress during the prepubertal period of life (21-32 days) on the acoustic startle response (ASR) were studied in outbred Wistar normotensives and rats with inherited stress-induced arterial hypertension (ISIAH) derived from them. Chronic variable stress (CVS) and repeated handling were used as chronic treatment. The obtained data showed a significantly attenuated ASR and a greater magnitude of prepulse inhibition (PPI) in juvenile and adult ISIAH compared to Wistar rats. The immediate effects of prolonged stress on the ASR were genotype-dependent. Young ISIAH rats exposed to both types of prepubertal stimulation had higher ASR than the age-matched controls. No significant stress-induced changes in the ASR were found in young Wistar rats. The long-lasting consequences of prolonged prepubertal stress were similar in the two strains and were determined by the specificity of stress stimulation: chronic handling had no effect on the ASR, while CVS enhanced it. The long-lasting effect of CVS experienced in prepubertal life appears to produce ASR changes similar to those seen in patients with posttraumatic stress disorder (PTSD). The magnitude of PPI increased from early age to adulthood and it was tolerant to environmental influences. The two rat strains did not differ in the rate of short-term habituation to repeated acoustic stimuli, which was unaffected by prepubertal stress. Evidence was obtained indicating that genetic and environmental background in childhood may contribute to the truncation of the startle response.

MAO A knockout attenuates adrenocortical response to various kinds of stress

The effect of a lack of the gene encoding monoamine oxidase A (MAO A) in transgenic Tg 8 mice on the corticosterone response to restraint, cold, water deprivation-induced, or social acute stress as well as chronic variable stress was studied. It was found that Tg 8 mice with genetic MAO A knockout and wild-type C3H/HeJ (C3H) strain showed similar plasma corticosterone resting level. MAO A knockout mice differed from C3H mice by attenuated response to restraint (60 min), cold (4 degrees C, 60 min), and water deprivation (48 h) as well as to a chronic (15 days) variable stress. No difference between Tg 8 and C3H strains in the response to psychosocial stress (encounters for 30 min of six previously isolated mice) has been found. ACTH administration to dexamethasone-pretreated mice produced a similar corticosterone effect in Tg 8 and C3H mice, indicating that the decreased stress response in MAO A-deficient mice was due rather to the central mechanisms regulating stress-induced ACTH release than to adrenocortical responsiveness to ACTH.

Brain serotonin metabolism during water deprivation and hydration in rats.

The effects of two-day water deprivation and hyperhydration (provision of 4% sucrose solution for 48 h) on levels of serotonin and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the midbrain and hypothalamus were studied in Wistar rats. The rates of diuresis (0.05 ± 0.01 and 0.84 ± 0.12 ml/h/100 g in water deprivation and hyperhydration respectively) and urine osmolality (1896 ± 182 and 50 ± 13 mOsm/kg) reflected increases and decreases in blood vasopressin levels. Water deprivation was associated with a significant increase in 5-HIAA levels in the midbrain and hypothalamus, along with a decrease in serotonin levels and a three-fold increase in serotonin catabolism (the 5-HIAA:serotonin concentration ratio). Hyperhydration induced moderate increases in serotonin and 5-HIAA levels in the hypothalamus with no changes in the midbrain. The blood corticosterone level doubled in water deprivation and decreased in hyperhydration. It is suggested that activation of the serotoninergic system induces a complex adaptive reaction in water deprivation, including mechanisms specific for the regulation of water-electrolyte homeostasis and non-specific stress mechanisms (vasopressin and corticoliberin secretion).

Effects of the mitochondria-targeted antioxidant SkQ1 on sexually motivated behavior in male rats

Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress and may be ameliorated by antioxidants. Here we examined effects of mitochondria-targeted antioxidant, SkQ1, on sexual motivation in 12-month-old Wistar and accelerated-senescent OXYS male rats. A change in behavioral activity of a male at a holed transparent partition with a receptive female on the other side was taken as an index of sexual motivation. The social behavior of male in same conditions with ovariectomised (OVXed) female and castrated male was investigated to differentiate sexually and socially motivated behavior. Behavioral response to social stimulus did not depend on age and genotype. No differences were found between 4- and 12-month-old Wistar males when sexual stimulus was presented; however, 12-month-old OXYS males demonstrated a lower propensity for sexual motivation as compared to 4-month-old OXYS rats and 12-month-old Wistar rats. We examined effects of SkQ1 on sexual motivation in 12-month-old male rats following prolonged supplementation begun at 1.5months of age (10, 50 or 250nmol/kg daily), a 45-day supplementation begun at 10.5months of age (50nmol/kg) and a 3-month supplementation begun at 9months of age (250nmol/kg). SkQ1 did not affect locomotor activity; however, it increased the time spent at the partition. A significantly higher measure of the motivational stage of sexual behavior was displayed following chronic preventive treatment at a dose of 50 and 250nmol/kg by OXYS rats. Chronic therapeutic treatment during 3months at a dose of 250nmol/kg was effective in age-accelerated OXYS rats too. These findings suggest an essential role for oxidative stress associated with mitochondrial dysfunction in the decline of sexually motivated behavior of male rats. Recovery from these impairments and/or their prevention enables a fully successful performance of the initial stage of male sexual behavior.

Prolonged Social Isolation and Social Instability in Adolescence in Rats: Immediate and Long-Term Physiological and Behavioral Effects

After weaning on the 21st day of life, Wistar rat pups were kept in groups of 4–5 individuals for six weeks (control group), in individual cages (social isolation group), or were subjected to alternate days of isolation and housing in groups of 10 rats with constant rotation of partners (social instability group). Some of the animals were then decapitated for investigations, while the remainder were tested and left undisturbed for two months in groups of 4–5 individuals. The animals were retested as adults. Body, thymus, and adrenal weight were measured, along with blood corticosterone levels at rest and in acute stress; basal testosterone levels, basal and stress systolic arterial blood pressure, and the amplitude and prepulse inhibition of the acoustic startle reaction were assessed, and the behavioral manifestations of anxiety and depression were evaluated. The results showed that social environment factors in adolescence affected the animals’ physiological and behavioral characteristics, some effects being transient and settling on subsequent housing in stable groups, others persisting into adulthood, and a third group becoming significant only as rats became adults.

The Genetic Control of Blood Pressure and Body Composition in Rats with Stress-Sensitive Hypertension

The genetic basis of the stress-sensitive arterial hypertension was investigated using the quantitative trait loci (QTL) approach. Two groups of F2 (inherited stress-induced arterial hypertension [ISIAH] × Wistar albino Glaxo [WAG]) hybrid males of different age (3–4 months old and 6 months old) were tested for blood pressure at rest and stressed conditions and for body composition traits. Several novel loci for the traits were determined. Some loci for blood pressure and organ weight were mapped to the same genetic region in rats of different age. The dynamic change of QTL effects in two rat groups of different age might reflect the process of stress-sensitive hypertension development.

Hypothalamic monoamines in cold stress on the background of changes in the activity of the nitric oxide system

The effects of the NO donor sodium nitroprusside and the NO synthase blocker L-ω-N-nitroarginine (LNA) on body temperature, hypothalamic monoamines, and plasma corticosterone in conditions of cooling were studied in Male Wistar rats. Reductions in body temperature on cooling, both after administration of sodium nitroprusside and LNA, were no different from those seen without treatment. The basal corticosterone level after treatment with sodium nitroprusside increased from 5.3 ± 2.2 to 29.1 ± 1.8 µg%. Cooling led to a multiple increase in corticosterone levels in all animals, both in control conditions and after treatment with sodium nitroprusside and LNA. Sodium nitroprusside significantly decreased the basal hypothalamic noradrenaline level, by 37%. Cooling of the animals in these conditions led to an additional drop in the noradrenaline level. Noradrenaline levels 48 h after cold stress applied to animals cooled after treatment with LNA or sodium nitroprusside were significantly higher than in those cooled without treatment. No changes in serotonin and 5-hydroxyindoleacetic acid levels were seen in these experiments. The basal dihydroxyphenylacetic acid and dopamine levels increased after treatment with sodium nitroprusside, by 379% and 239% respectively. No dopamine response to cold was observed, though the dihydroxyphenylacetic acid level in the control group and animals treated with LNA increased. Thus, cold stress did not reveal differently directed directions for the actions of the NO donor and the NO synthase blocker, as seen with other types of stress.

Brain catecholamines and the hypothalamo-hypophyseal-adrenocortical system in inherited arterial hypertension

Rats with inherited stress-induced arterial hypertension (NISAG rats) and normotensive Wistar rats were used for studies of age-related changes in arterial pressure (BP), in the activity of the hypothalamo-hypophyseal-adrenocortical system (HHAS), and noradrenaline levels in brain structures involved in regulating these functions, with the aim of identifying possible relationships between them. It is suggested that the noradrenaline deficiency seen at the age of four weeks in the hypothalamus and medulla oblongata in NISAG rats is involved in the pathogenesis of hypertension and in disturbing the function of the HHAS. Transient increases in brain catecholamine synthesis in the fourth week of life lead to prolonged reductions in BP and complete recovery of HHAS responses to stress in adult animals. Correction of BP and HHAS function is accompanied by changes towards the normal in noradrenaline levels in the hypothalamus and medulla oblongata and in the numbers of α1-adrenoceptors in the medulla oblongata.

Social isolation during peri-adolescence or adulthood: effects on sexual motivation, testosterone and corticosterone response under conditions of sexual arousal in male rats.

Reproductive functions in adult organism are known to be affected by different factors. Effects of social environment at the postnatal ontogenesis attract particular attention since it has deep impact on the development of physiological and emotional state of an individual. Effects of chronic social isolation at different ages on male sexual motivation, testosterone and corticosterone response under conditions of sexual arousal were studied in Wistar rats. After weaning at the 21st [corrected] day of age, rats of one group were isolated for six weeks and after that they were housed in groups of five per cage for ten weeks (Iso3-9). Rats of the second group were housed in groups of five animals per cage till 13 weeks of age, and then they were isolated for six weeks (Iso13-19). Rats of the control group were housed in groups during the experiment. Adult 19 week- old male rats were tested under conditions of sexual arousal. The expression of sexual motivation was estimated as the behavioral activity of a male at the transparent perforated partition separating a receptive female. Isolation of adult male rats reduced the number of approaches to the partition, while the period of time a male spent at the partition was not changed and testosterone response was enhanced as compared to control rats. Chronic social isolation during peri-adolescence reduced sexual motivation and prevented arousal-induced elevation of testosterone. Plasma corticosterone increases at sexual arousal in the two groups of isolated rats did not differ from that in controls. Our results are evidence that social isolation during the post-maturity stage (Iso13-19) did not diminish the manifestation of sexual motivation and hormonal response to a receptive female, while isolation during peri-adolescence attenuated behavioral and hormonal expression of sexual arousal in adult males.