Edited by: Hubert Vaudry, University of Rouen, France
Reviewed by: James A. Carr, Texas Tech University, USA; Dóra Zelena, Institute of Experimental Medicine, Hungary
*Correspondence: Nadezhda D. Goncharova, Research Institute of Medical Primatology of Russian Academy of Medical Sciences, Veseloye 1, Adler, Sochi 354376, Krasnodarskii Krai, Russia. e-mail:
This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Endocrinology.
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The hypothalamic–pituitary–adrenal (HPA) axis plays a key role in adaptation to environmental stresses. Parvicellular neurons of the hypothalamic paraventricular nucleus secrete corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) into pituitary portal system; CRH and AVP stimulate adrenocorticotropic hormone (ACTH) release through specific G-protein-coupled membrane receptors on pituitary corticotrophs, CRHR1 for CRH and V1b for AVP; the adrenal gland cortex secretes glucocorticoids in response to ACTH. The glucocorticoids activate specific receptors in brain and peripheral tissues thereby triggering the necessary metabolic, immune, neuromodulatory, and behavioral changes to resist stress. While importance of CRH, as a key hypothalamic factor of HPA axis regulation in basal and stress conditions in most species, is generally recognized, role of AVP remains to be clarified. This review focuses on the role of AVP in the regulation of stress responsiveness of the HPA axis with emphasis on the effects of aging on vasopressinergic regulation of HPA axis stress responsiveness. Under most of the known stressors, AVP is necessary for acute ACTH secretion but in a context-specific manner. The current data on the AVP role in regulation of HPA responsiveness to chronic stress in adulthood are rather contradictory. The importance of the vasopressinergic regulation of the HPA stress responsiveness is greatest during fetal development, in neonatal period, and in the lactating adult. Aging associated with increased variability in several parameters of HPA function including basal state, responsiveness to stressors, and special testing. Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory and requires further research. Many contradictory results may be due to age and species differences in the HPA function of rodents and primates.
The hypothalamic–pituitary–adrenal (HPA) axis is a key adaptive neuroendocrine system. Regulation of glucocorticoid secretion through adrenocorticotropic hormone (ACTH) is critical to life and essential to maintain the mammalian response to stressor (Pedersen et al.,
In resting conditions, activity of the HPA axis shows circadian and ultradian changes with pulsatile glucocorticoid secretion that is greater in amplitude during the phase of wakefulness. This leads to higher average levels of glucocorticoids during the day in humans and most other primates and to higher activity of the HPA axis during the night in rodents (Goncharova et al.,
While the acute stress activation of the HPA axis is critical for life, chronic exposure to stressors leads to its excessive stimulation and hypercortisolemia. Hypercortisolemia plays a pathophysiological role in the development of a variety of stress-related diseases: psychiatric, reproductive, immune, metabolic, and others. It is a major factor in aging and age-related pathology (Chrousos,
Corticotrophin releasing hormone is the main physiological regulator of the HPA axis in basal conditions and in response to most acute stressors (Jacobson et al.,
The collection of CRH-producing neurons (CRH neurons) of the PVN is a key center of the central nervous system, integrating the neuroendocrine effects of stress, and a key part of the HPA axis. On the one hand, the CRH neuron is under the regulatory influence of numerous afferent nerve pathways that carry information about the stressor. In addition, it is regulated by glucocorticoids and it is the central link of the autoregulation mechanism in the HPA axis.
The CRH neuron receives projections from ascending catecholaminergic pathways including noradrenergic projections from the A2 noradrenergic cell group within the nucleus of the solitary tract and the locus ceruleus. It also receives input from areas of the limbic system, notably the bed nucleus of the stria terminalis, the hippocampus, and the amygdala (Herman et al.,
Feedback mechanism plays an essential role in the regulation of CRH production and in limiting the stress response. The central sensors of feedback to the HPA axis are two corticosteroid receptors, the high-affinity mineralocorticoid receptor (MR) and the low-affinity glucocorticoid receptors (GR), which are expressed in the brain and on the corticotrophs of the pituitary (Ratka et al.,
While it is generally accepted that CRH is a critical coordinator of HPA axis function in resting conditions and in response to stress (Aguilera,
Knowledge of the functional anatomy, physiology, and pathophysiology of AVP in the regulation of the HPA axis is mainly based on studies carried out on rodents. There are two major vasopressinergic systems in the brain. The first system consists of hypothalamic magnocellular neurons in the PVN and supraoptic nucleus, which project to the neurohypophysis and deliver AVP and oxytocin to the peripheral circulation; it is largely responsible for the peripheral actions of AVP that maintain water homeostasis and blood pressure (Knepper,
The actions of AVP are mediated through interaction with specific plasma membrane receptors of target cells that have been identified and cloned (Jard et al.,
The ability of both neuropeptides CRH and AVP to stimulate the secretion of ACTH has been demonstrated in humans (DeBold et al.,
Acute immobilization stress has been observed to lead to up-regulation of AVP mRNA along with up-regulation of CRH mRNA expression in parvicellular neurons of the PVN (Bartanusz et al.,
The precise role of AVP production in response to stress remains controversial because most studies have involved indirect or correlative measurements of activation of AVP-producing neurons after exposure to stress (DeBold et al.,
Nevertheless, several studies do not support the conclusion of an important role for AVP in the regulation of HPA axis stress responsiveness. Animals in some studies using modern genetic and pharmacological models to create an AVP deficit have, nevertheless shown a normal response of the HPA axis in acute stress, specifically to restraint, resident-intruder, and LPS stressors (Lolait et al.,
In other studies using genetic and pharmacological models of AVP deficit the pituitary–adrenal responses to acute stress were substantially reduced. Thus, recent studies with the V1b receptor knockout mice demonstrated reduced plasma levels of ACTH and corticosterone or only ACTH in response to insulin-induced hypoglycemia (Lolait et al.,
Findings from studies of the role of AVP in responsiveness of the HPA axis in acute stress using V1b receptor antagonists in rodents are consistent with studies of naturally AVP-deficient Brattleboro rats (Zelena et al.,
Age can also influence the importance of AVP for the HPA axis response to acute stress. Reduced ACTH and corticosterone release was observed in AVP-deficient rats in the neonatal period, while adult rats of the same strain demonstrated a normal response of the pituitary–adrenal axis to LPS injection (Zelena et al.,
There is a wide range of studies on the role of AVP in the HPA axis regulation not only in response to acute stressors but during basal conditions. Studies using AVP immunoneutralization have not identified a role of AVP in basal ACTH regulation (Ono et al.,
Regulation of V1b receptors in the pituitary gland appears to play a major role in corticotroph responses to chronic stressors, as a good correlation has been established between the concentration of the receptor and the secretion of ACTH by the pituitary gland (Aguilera,
Numerous studies performed in rats have revealed a shift of hypothalamic CRH/AVP signal in favor of AVP in some chronic stress states. This is manifested by enhanced AVP synthesis in CRH-producing cells in parvicellular neurons of the PVN after repeated restraint (Whitnall,
The results of direct manipulation of the HPA axis reinforce the idea that chronic stress induces a shift of the hypothalamic CRH/AVP signal in favor of AVP. Prolonged administration of CRH by osmotic minipumps led to a reduction in CRH receptor number in the pituitary corticotrophs of control rats (Tizabi and Aguilera,
Repeated restraint stress or repeated hypertonic saline injections were found to produce sustained increases in the expression of V1b receptor mRNA in the pituitary (Rabadan-Diehl et al.,
The sensitivity of CRH and AVP transcription to glucocorticoid feedback is markedly different (Bilezijian et al.,
All these findings support the proposal that CRH plays a predominantly permissive role in the HPA axis regulation in conditions of chronic stress, but AVP is a dynamic modulator of ACTH release (Plotsky,
Some recent studies of chronic stress in naturally AVP-deficient Brattleboro rats, suggest that the role of V1b and AVP in adaptation of the HPA axis to chronic stress may not be as convincing as first thought. Experiments on Brattleboro rats and control heterozygous littermates utilized three different chronic stress models: repeated restraint to produce physical–psychological stress (Zelena et al.,
Perhaps the contradictory results can be explained in terms of age and species differences in the HPA function of rodents and primates, including humans. Some evidence suggests that AVP is the main regulator of the HPA axis during the perinatal period (Zelena et al.,
Extensive clinical and experimental data indicate variation in the importance of AVP in regulation of the HPA axis, including its stress responsiveness, at different stages of ontogeny and under different physiological conditions. The role of AVP in regulation of the HPA axis in the fetus has been described only in a few studies (Carey et al.,
Developmental studies have shown that neonatal rodents (Yi and Baram,
Such important physiological conditions of the organism as pregnancy and lactation are of considerable interest in terms of vasopressinergic regulation of stress reactivity of the HPA axis. It is well known that the HPA axis response to stressors is markedly attenuated in late pregnancy and during lactation period in women (Altemus et al.,
Gestation and early postnatal periods, as we know, are the most vulnerable periods of ontogenesis in terms of programing disruptions of the HPA axis for adulthood (Schmidt et al.,
It is generally accepted that mainly hyperactivation of the HPA axis occurs during aging. In small laboratory animals hyperactivation of the HPA axis in the aging process develops at all levels of the system. Thus, aged rodents demonstrated elevated resting ACTH and corticosterone plasma levels (Sapolsky et al.,
These have been expressed mainly as increases in the maximum peak values of plasma corticosterone rise and the prolongation of elevated corticosterone secretion (Sapolsky et al.,
Hyperactivation of the HPA axis during aging in humans and non-human primates is generally associated with elevated plasma levels of ACTH and cortisol in basal conditions (Sapolsky and Altman,
It should be noted that aging is associated with an increase in the variability of disturbances in the HPA axis both in primates and rodents but to a greater extent in humans and non-human primates than in rodents. Many authors have failed to observe significant age-related changes in basal plasma levels of ACTH and cortisol in humans (Ohashi et al.,
Some researchers have found higher responses to acute psycho-emotional stress in physically untrained aged individuals (Traustadóttir et al.,
At the same time, no age-related differences in ACTH and cortisol levels in response to acute psychosocial stress have been reported in postmenopausal women compared to young women (Kudielka et al.,
Experiments on healthy non-human primates (
It should be noted that a striking difference in physiology of the HPA axis between primates and rodents is the secretion of large amounts of DHEA and DHEAS by the primate adrenal cortex, which undergoes a decline with age (Orentreich et al.,
Significant variability has been found with respect to age-related changes in circadian rhythms of ACTH and glucocorticoid secretion both in humans and animals. While a number of studies have failed to show marked circadian disorders of cortisol and ACTH in humans and non-human primates (Chambers et al.,
The master circadian clock is located in the SCN of the hypothalamus. Its activity is synchronized with the natural day–night cycle, and it coordinates the circadian rhythms of the body, including the HPA axis rhythm (Reppert and Weaver,
Age-related changes in AVP production vary depending on location in the brain. While secretion of AVP decreases with aging in the SCN of animals and humans (Cai et al.,
In the literature there are several studies that investigated the role of the AVP/V1b receptor system in the regulation of stress responsiveness of the HPA axis with aging. Most of these studies have been performed in experiments on rodents. Features of vasopressinergic regulation of stress responsiveness of the HPA axis during aging has been studied significantly less in humans and non-human primates.
On the other hand, the idea that secretion of AVP in the PVN can increase with aging is evidenced by the results of studies on the role of AVP in the regulation of stress reactivity of the HPA axis, performed mainly on rodents. Thus, some reports in the literature describe work with rats of the Fischer-344/N strain, in which aging is associated with a progressive decline in hypothalamic CRH production associated with increased production of AVP (Cizza et al.,
Subsequent studies have confirmed the important role of AVP expressed in parvicellular neurons of the PVN in the regulation of ACTH secretion in response to stimulus. Application of the combined DEX/CRH test to old male Wistar rats resulted in excessive release of ACTH and corticosterone as compared to young rats. Administration of a V1b receptor antagonist between the dexamethasone and CRH injections blocked the effect (Hatzinger et al.,
Another study has demonstrated an increase in the content of AVP within the PVN in basal conditions. The approximately twofold increase correlated with an increase of ACTH and corticosterone basal plasma levels in old rats (Keck et al.,
Some of the contradictory results reported in the above papers may by attributable to individual differences in HPA axis function both in resting and stress conditions. Thus, in the study of Meijer et al. (
Thus, reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging in rodents are contradictory, suggesting (a) the possible increase of the AVP production in the PVN for aged rodents, (b) the possible lack of any age changes in the AVP secretion in basal and stress conditions, and (c) the possible reduced basal AVP production along with the CRH hypersecretion.
Only a few studies have addressed age-related changes in vasopressinergic regulation of HPA axis stress reactivity in humans and non-human primates (Raskind et al.,
It has been noted that the healthy elderly exhibit a more pronounced adrenocortical response to hypertonic saline infusion than young people (Raskind et al.,
Interestingly, chronic administration of DHEA to healthy young men significantly increased exercise-induced release of AVP along with ACTH and cortisol secretion (Deuster et al.,
Recent experiments on non-human primates (Goncharova,
The attempt to understand the mechanism of decreasing stress reactivity of the pituitary–adrenal axis with aging led to a series of experiments with the administration of a standard dose of CRH and AVP (1 μg/kg b.w., intravenously) to young and old female rhesus monkeys at different times of day (09:00 and 15:00 h). The response of the pituitary–adrenal axis to the injection of CRH revealed a circadian rhythm with a more pronounced response in the afternoon; this rhythm was not affected by aging (Goncharova,
The role of CRH and AVP in the stimulation of ACTH secretion varies depending upon the species. For humans, non-human primates, and rats CRH seems to be a more important secretagogue than AVP, in humans, all parvicellular neurons of the PVN, which produce CRH in the basal conditions, produce AVP as well, whereas in rats not more than half produce AVP.
AVP is an important regulator of the ACTH response to acute stress. AVP contributes to the acute ACTH secretion to stress in a context-specific manner. AVP is needed for the acute ACTH secretion for most of the known stressors.
Current data on the role of AVP in the regulation of HPA axis responsiveness to chronic stress in adulthood are contradictory and require further research.
The importance of the vasopressinergic regulation of stress responsiveness of the HPA axis is elevated during the fetal development, in neonatal period, and in the lactating adult.
Aging is associated with increased variability in several parameters of HPA axis function including basal state, responsiveness to stressors, and special testing. This increased variability in the aged compared to normal adults has been observed in some form in multiple species including rodents, non-human primates, and humans. For the most experiments on rodents, the hyperactivation of the HPA axis was observed at all levels of the HPA organization with aging under the basal and stress conditions. With healthy aging of non-human primates and humans the HPA hyperactivation is usually associated with the increase of the cortisol level in the evening time, the slight changes in the regulation of the HPA axis by glucocorticoid feedback with relative hypercortisolemia due to the decline in secretion of the adrenal antagonists of cortisol – DHEA and DHEAS.
Reports on the possible role of the AVP/V1b receptor system in the increase of HPA axis hyperactivity with aging are contradictory, suggesting
the possible increase of the AVP production in the PVN for aged rodents and humans, the possible lack of any age changes in the AVP secretion in basal and stress conditions, the possible reduced basal AVP production along with the CRH hypersecretion.
Age-related changes in response of the HPA axis to the moderate acute restraint stress were observed in rhesus monkeys with much higher increase of ACTH and cortisol secretion in young monkeys in response to the stress imposed at 15:00 h. In addition, these age changes were associated with age-related disturbances in vasopressinergic regulation.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.