No abstract

We have investigated aging of the hypothalamic-pituitary-adrenal (HPA) axis in female rhesus monkeys that differ in adaptive behavior. Plasma cortisol (F) and dehydroepiandrosterone sulfate (DHEA-S) concentrations under basal conditions and under acute psycho-emotional stress were evaluated in blood plasma of young (6-8 years) and old (20-27 years) female rhesus monkeys with various types of adaptive behavior (aggressive, depression-like, and average). We have found that the age-related changes in the HPA axis of monkeys with depression-like behavior were accompanied by the maximal absolute and relative hypercortisolemia under both basal conditions and stress. Moreover, young aggressive monkeys, in comparison with young monkeys of other behavior groups, demonstrated the highest plasma levels of DHEA-S and the lowest molar ratios between F and DHEA-S. Thus, age-related dysfunctions of the HPA axis are associated with adaptive behavior of animals.

Age-specific differences in the reaction of the hypothalamic-pituitary-adrenal system to acute psychoemotional stress (immobilization) was studied in female rhesus macaques aged 6-8 and 20-27 years at different time of the day. The reactivity of the hypothalamic-pituitary-adrenal system during immobilization at 15.00 was lower in old animals, while at 9.00 there were no age-specific differences or the reactivity was higher in old animals.

The study of the mechanisms underlying the increased vulnerability of the individual to stressful environmental factors in different age periods is of great relevance for prevention and effective treatment of stress-dependent diseases that are widespread in the population of aging individuals. The purpose of our study was to investigate the individual and age-related features of the glucocorticoid negative feedback in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, the key adaptive neuroendocrine system, in experiments with physically healthy young and old female rhesus monkeys with administration of mineracorticoid receptor (fludrocortisone) and glucocorticoid receptor (dexamethasone) agonists. We studied the monkeys with increased trait anxiety and depression-like behavior (DAB) characterized, as previously was shown, by the increased vulnerability to acute stress and the animals with normal standard behavior (SB) as the control. The pronounced individual differences in the reaction of HPA axis to fludrocortisone and dexamethasone in young animals were found. Young animals with DAB showed a lower sensitivity of HPA axis to the inhibitory effect of both fludrocortisone and dexamethasone compared with young animals with SB. At the same time, there were no significant intergroup differences in the concentration of ACTH and cortisol in response to placebo injection, i.e., in basal conditions. The old individuals with DAB demonstrated the essential relative resistance of HPA axis to fludrocortisone test and higher basal plasma levels of cortisol and ACTH in the evening (the period of HPA axis low circadian activity) compared to old SB animals. In the same time, the intergroup differences in the response of HPA axis to dexamethasone administration were leveled due to age-related increase in sensitivity of HPA axis to dexamethasone in animals with DAB. These data testify the pronounced intergroup and age differences in the feedback regulation of HPA axis, presumably resulting from unequal individual, and age-related changes in the activity of mineralcorticoid and glucocorticoid receptors in the brain structures supporting the functions of HPA axis. The maximum age disorders in functioning of the negative feedback mechanism in the regulation of HPA axis are characteristic of animals with DAB, which, apparently, underlie the increased vulnerability of these animals to stress exposure.

Individual features of the response of the hypothalamic-pituitary-adrenal axis (HPAA) to repeated moderate stress exposure (daily 2-h restraint stress for 10 days) was studied in young female rhesus monkeys with healthy normal behavior and combined group of female rhesus monkeys with abnormal depression-like and anxious behavior. No between-group differences in the response of ACTH and cortisol were found on day 1. On day 10, a rapid and less pronounced increase in ACTH secretion was observed in all animals in comparison with day 1. Analysis of between-group differences in HPAA response showed higher increase in ACTH level and lower increase in cortisol concentration in animals with depression-like and anxious behavior. These changes were similar to the previously described differences in the response of the adenohypophysis and adrenal cortex to acute restraint stress in old monkeys with similar behavior. Thus, individuals with depression-like and anxious behavior demonstrate impaired stress-induced reactivity of HPAA as early as in young age.

Experimental study was carried out on young mature (6-8 years) and old (21-27 years) rhesus macaques with anxious and depression-like behavior and with standard (control) adaptive behavior. The responce of the adenohypophysis to arginine vasopressin depended on age and the type of adaptive behavior. Young animals with standard behavior demonstrated much higher concentrations of ACTH in the peripheral plasma in response to arginine vasopressin than old animals. The secretion of ACTH was higher in young and old animals with anxious and depressive-like adaptive behavior and they exhibited no age-specific differences in reaction to arginine vasopressin, which were observed in control animals. Preinjection of vasopressin V1b receptor antagonist to a female with high anxiety sharply reduced ACTH secretion in response to insulin-induced hypoglycemia in comparison with ACTH secretion under the same conditions without antagonist injection. These results suggested that the vasopressinergic system of animals with anxious and depressive behavior plays an important role in the regulation of ACTH secretion and in activity of the hypothalamic-pituitary-adrenal system in general.

Stress adaptation is fundamental for health, and the hypothalamic-pituitary-adrenal axis (HPA) is one of its main mechanisms. Considerable data indicate that arginine vasopressin (AVP) related disturbances of stress adaptation can occur with aging. However, most studies of such kind have been performed on rodents, give contradictory results and fail to consider individual characteristics of the animals. The purpose of this study was to investigate individual HPA responsiveness to acute stress and its vasopressinergic regulation in old female rhesus monkeys that differ in their behavioral responses to stress. Animals with depression-like or anxiety-like behavior (DAB) responded with higher plasma levels of ACTH and AVP, lower levels of corticosteroids and higher cortisol/DHEAS molar ratios to restraint stress and to insulin-induced hypoglycemia compared with animals with healthy adaptive behavior. AVP and ACTH dynamics were closely correlated in most animals. AVP treatment produced differences in HPA responses similar to those produced by the stressors. The ACTH response to hypoglycemic stress in the DAB animal with highest HPA responsiveness was dramatically reduced by prior administration of a V1b receptor antagonist. These results suggest that the dysfunctions of HPA observed in old animals with DAB are caused by increased tone of the vasopressinergic system in regulation of HPA stress reactivity.

Comparative studies on the functioning of the adrenal cortex in female rhesus macaques (Macaca mulatta) of different ages are reported - animals were aged 6-9 years (young adults; n = 5) and 20-26 years (old adults; n = 5). Corticosteroid concentrations (cortisol (F) and dehydroepiandrosterone sulfate (DHEAS)) were determined by specific radioimmunological and immunoenzyme methods in basal conditions, after acute stress (insulin-induced hypoglycemia, 2-h movement restriction), and after administration of dexamethasone. Basal F levels showed no marked age differences, while DHEAS concentrations in older animals decreased sharply. These animals also demonstrated weakened adrenal cortex responses to movement restriction, giving rise to delays in reaching peak F and DHEAS levels and decreases in the areas under their response curves (AUC) during the 4-h study period. In the dexamethasone test, the hypothalamo-hypophyseal-adrenal system of monkeys aged 20-26 years was relatively resistant to the suppressing effect of glucocorticoids via the negative feedback mechanism. It is suggested that disruption of feedback in the system controlling adrenal cortex function may be at least partially due to the development of peripheral blood steroid dysbalance with aging, this consisting particularly of a decrease in the DHEA (DHEAS) level; this steroid is known for its neurological activity.