Dóra Zelena

Vasopressin is a ubiquitous molecule playing an important role in a wide range of physiological processes thereby implicated in the pathomechanism of many disorders. Its effect is well characterized through V2 receptors, which regulates the water resorption in kidney, while its vasoconstrictory effect through V1a receptor also received a lot of attention in the maintenance of blood pressure during shock. However, the most striking is its central effect both through the V1b receptors in stress-axis regulation as well as through V1a receptors regulating many aspects of our behavior (e.g., social behavior, learning and memory). Vasopressin has been implicated in the development of depression, due to its connection with chronic stress, as well as schizophrenia because of its involvement in social interactions and memory processes. Epigenetic changes may also play a role in the development of these disorders. The possible mechanism includes DNA methylation, histone modification and/or micro RNAs, and these possible regulations will be in the focus of our present review.

Stress adaptation is of utmost importance for the maintenance of homeostasis and, therefore, of life itself. The prevalence of stress-related disorders is increasing, emphasizing the importance of exploratory research on stress adaptation. Two major regulatory pathways exist: the hypothalamic–pituitary–adrenocortical axis and the sympathetic adrenomedullary axis. They act in unison, ensured by the enormous bidirectional connection between their centers, the paraventricular nucleus of the hypothalamus (PVN), and the brainstem monoaminergic cell groups, respectively. PVN and especially their corticotropin-releasing hormone (CRH) producing neurons are considered to be the centrum of stress regulation. However, the brainstem seems to be equally important. Therefore, we aimed to summarize the present knowledge on the role of classical neurotransmitters of the brainstem (GABA, glutamate as well as serotonin, noradrenaline, adrenaline, and dopamine) in stress adaptation. Neuropeptides, including CRH, might be co-localized in the brainstem nuclei. Here we focused on CRH as its role in stress regulation is well-known and widely accepted and other CRH neurons scattered along the brain may also complement the function of the PVN. Although CRH-positive cells are present on some parts of the brainstem, sometimes even in comparable amounts as in the PVN, not much is known about their contribution to stress adaptation. Based on the role of the Barrington’s nucleus in micturition and the inferior olivary complex in the regulation of fine motoric—as the main CRH-containing brainstem areas—we might assume that these areas regulate stress-induced urination and locomotion, respectively. Further studies are necessary for the field.

In adults, vasopressin exerts an anxiogenic effect, but less is known about the perinatal period. As a sign of distress, rat pups emit ultrasonic vocalizations when they are separated from their mothers, known as maternal separation-induced ultrasonic vocalization (MS-USV). Previously, reduced MS-USV was reported in 7–8-day-old genetically vasopressin-deficient Brattleboro rats. Here, we aimed to examine the contributing vasopressin receptor (VR) subtypes using Wistar pups. MS-USV was recorded for 10 min, 30 min after vasopressin (V) 1aR, V1bR or V2R antagonist treatment (SR49059, SSR149415, SR121463B; 3, 10 and 30 mg/kg, intraperitoneal). Sedation was studied by the righting reflex and negative geotaxis, and finally, the stress hormone levels were measured by radioimmunoassay. The vasopressin-deficient pups showed decreased MS-USV and adrenocorticotropin levels even after a saline injection, with unchanged corticosterone levels. Thirty mg/kg of V1aR-antagonist increased the corticosterone levels. All V1bR antagonist doses decreased the MS-USV and adrenocorticotropin, while 10 + 10 mg/kg of V1aR and V1bR antagonists decreased MS-USV without influencing the stress hormones. Three mg/kg of V2R antagonist enhanced MS-USV, while 30 mg/kg increased the stress hormone levels. We confirmed that vasopressin deficiency already caused anxiolytic effects in pups. V1bRs are the most important player in connection with their adrenocorticotropin (ACTH)-regulatory role, but a combination of V1aR and V1bR antagonists might be also beneficial through other mechanisms, reducing the possibility of side effects. In contrast, antagonizing the V2Rs may be stressful due to an induction of imbalance in saltwater homeostasis.

The hypothalamic components of the hypothalamo–pituitary–adrenal axis (HPA) are corticotropin-releasing hormone (CRH) and vasopressin. To test the hypothesis that HPA regulation changes with age, we compared ether and bacterial lipopolysaccharide (LPS) injection induced stress reactions in adult and 10-day-old Brattleboro rats, which naturally lack vasopressin owing to mutation of the gene (di/di). The LPS stimulus was used also with V_1b receptor antagonist pretreatment (SSR149415). In adult di/di or V_1b pretreated rats, we observed normal pituitary and adrenocortical secretory responses, while in all 10-day-old rats stress-induced serum corticosterone increases were marked, but adrenocorticotropin (ACTH) increases were significantly smaller. Compared to control pups the adenohypophysis of the 10-day-old di/di rats responded normally to CRH, but their adrenal glands were hyper-responsive to ACTH, while in adults there was greater secretion at both levels with no difference between the genotypes. The serum transcortin level was higher in adults than pups, with the di/di pups having higher transcortin levels than controls. Hence, using the same stressors in adults and pups with both a genetic model and pharmacological pretreatment, we have shown that the role of vasopressin in ACTH regulation is more important during the neonatal period than in adulthood. Blunted hypophysial sensitivity to CRH and similar adrenal gland sensitivity to ACTH in the pups compared to adults suggest that hypothalamic factors could be responsible for the neonatal stress hyporesponsive period.

Adaptation to a constantly changing environment is fundamental to every living organism. The hypothalamic–pituitary–adrenocortical (HPA) axis is a key component of the adaptation process. The present study tests the hypothesis that vasopressin (AVP) is required for the HPA response to acute stimuli. To accomplish this, naturally AVP-deficient Brattleboro rats were exposed to a wide range of stimuli and their HPA response was compared with heterozygous littermattes. The circadian rhythmicity of plasma ACTH and corticosterone was not different between the two genotypes. The ACTH and corticosterone response to volume load, restraint or aggressive attack were decreased in AVP-deficient rats. The stress-induced increase in ACTH, but not corticosterone, was significantly impaired in AVP-deficient animals after novelty, elevated plus-maze, forced swim, hypoglycaemia, ulcerogenic cold immobilisation, lipopolysaccharide, hypertonic saline and egg white injection. The HPA response to social avoidance, ether inhalation and footshock was not different between the genotypes. In vitro, the hypophysis of AVP-deficient animals showed a reduction in stimulated ACTH production and their adrenal glands were hyporeactive to ACTH. A dissociation between the ACTH and corticosterone response was observed in several experiments and could not be explained by an earlier ACTH peak or enhanced adrenal sensitivity, suggesting the existence of paraadenohypophyseal neuroendocrine regulators. Loss of AVP affected the HPA response to a wide variety of stressors. Interestingly, the contribution of AVP to the HPA response was not specific for, nor limited to, a known stressor category. Thus, there is a context-specific requirement for AVP in stress-induced activation of the HPA axis.

Anomalies in hormonal and neurotransmitter status during perinatal period can lead to lifespan alterations in the central nervous system. Vasopressin is present early in the brain and has various mitogenic, metabolic and physiological actions, e.g. in water homeostasis or in the regulation of the hypothalamo-pituitary-adrenal (HPA) axis. Therefore we examine the possible role of vasopressin in perinatal development with special attention to the influence of maternal genotype and to the HPA axis regulation. We compared homozygous vasopressin deficient (di/di) Brattleboro rats to their heterozygous (di/+) littermates both from di/+ and di/di mother. Higher locomotion due to reduced adaptation was present at preweaning. During the first 10 days of life the di/di pups from di/di mother were the smallest, while in the later perinatal period the genotype of the pups became the more important determinant of the somatic development, namely the di/di pups from both mothers had reduced weight gain. Generally the lack of vasopressin in the pups fastened the somatic development (pinna detachment, eye and ear opening, incisor eruption) however the neurobehavioral development (palmar grasp reflex, righting reflex, negative geotaxis, etc.) was not influenced profoundly by either the mother's or the pup's genotype. The lack of vasopressin in pups abolished the 24 h maternal separation induced adrenocorticotrop hormone (ACTH) elevation while the accompanying corticosterone rises were even higher. The vasopressin deficiency of the mother reduced the resting ACTH and all corticosterone levels in all pups. So we can conclude that the lack of vasopressin speeds up the development, probably there is a greater drive for self-sufficiency in these animals. The mother's vasopressin deficiency reduced the HPA axis reactivity of the pups. The role of vasopressin in the HPA axis regulation is important during the perinatal period independently from the mother's genotype. The large discrepancy between ACTH and corticosterone regulation requires further studies.