. Role of hypothalamic inputs in maintaining pituitary-adrenal responsiveness in repeated restraint. Am J Physiol Endocrinol Metab 285: E1110-E1117, 2003; 10.1152/ ajpendo.00219.2003.-The role of hypothalamic structures in the regulation of chronic stress responses was studied by lesioning the mediobasal hypothalamus or the paraventricular nucleus of hypothalamus (PVH). Rats were acutely (60 min) and/or repeatedly (for 7 days) restrained. In controls, a single restraint elevated the plasma adrenocorticotropin (ACTH), corticosterone, and prolactin levels. Repeated restraint produced all signs of chronic stress, including decreased body and thymus weights, increased adrenal weight, basal corticosterone levels, and proopiomelanocortin (POMC) mRNA expression in the anterior pituitary. Some adaptation to repeated restraint of the ACTH response, but not of other hormonal responses, was seen. Lesioning of the mediobasal hypothalamus abolished the hormonal response and POMC mRNA activation to acute and/or repeated restraint, suggesting that the hypothalamo-pituitaryadrenal axis activation during repeated restraint is centrally driven. PVH lesion inhibited the ACTH and corticosterone rise to the first restraint by ϳ50%. In repeatedly restrained rats with PVH lesion, the ACTH response to the last restraint was reduced almost to basal control levels, and the elevation of POMC mRNA level was prevented. PVH seems to be important for the repeated restraint-induced ACTH and POMC mRNA stimulation, but it appears to partially mediate other restraintinduced hormonal changes. adrenocorticotropin; corticosterone; mediobasal hypothalamus; paraventricular nucleus; proopiomelanocortin; rat IN ACUTE STRESS, the hypothalamic paraventricular nucleus of hypothalamus (PVH) is known to be a key site in the activation of the hypothalamo-pituitary-adrenal (HPA) axis by providing the hypophysiotropic neuropeptides corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) to stimulate ACTH secretion from the anterior pituitary (see Ref. 2). Various stress paradigms act through different pathways, because in some cases the elimination of PVH abolished acute stress-induced ACTH elevation [hemorrhage (10), early response after bacterial lipopolysaccharide (13), elevated platform stress (28)], but with some other stressors, considerable ACTH and/or corticosterone elevation occurs even after lesioning the PVH [hypovolemia (7), ether (8, 27, 29), immobilization, electrical stimulation of the skin (14), footshock, IL-1␤ (40)].Chronic stress can be elicited by repeated exposure to short-acting stressors or by action of a sustained or persistent stimulus, e.g., a disease. Chronic stress is characterized by the classical symptoms of decreased body and thymus weight and a parallel increase in adrenal size and width of the adrenal cortex, consistent with chronic activation of the HPA axis (6, 12). The sustained activation of the CRH/AVP cells in the PVH is suggested to have a central role during chronic stress-induced HPA axis activation, and t...

In adulthood the hypothalamo-pituitary-adrenal axis is controlled by both CRH and arginine vasopressin (AVP). However, in neonates CRH secretion is very low, whereas AVP secretion is fully functional. This suggests that the role of AVP is more pronounced in young than in adult rats. We investigated the role of AVP by studying stress responses in 5, 10, and 20-d-old AVP-deficient Brattleboro rats. Two different stressors were applied: 24-h maternal separation and Hypnorm Grove Oxford UK injections. In heterozygous controls (that do express AVP), both stressors increased plasma ACTH and corticosterone. The ACTH stress response disappeared in AVP-deficient rats, demonstrating that during the perinatal period, the secretion of this hormone is controlled by AVP. Surprisingly, corticosterone responses remained intact in AVP-deficient rats. Similar findings were obtained after 1-, 4-, 12-, and 24-h long maternal separations. Thus, preserved corticosterone stress responses were not explained by changes in the timing of ACTH secretion. In vitro experiments suggested that the dissociation of ACTH and corticosterone stress responses can only be partly explained by higher ACTH responsiveness of the adrenal cortex in AVP-deficient rats. Together, our results show that in neonatal periods, AVP is crucial for the expression of ACTH stress responses, but neither AVP nor ACTH is necessary for the induction of corticosterone stress responses. Discrepant ACTH and corticosterone stress responses may reflect compensatory mechanisms activated by AVP deficiency, but disparate findings suggest that they rather depict a neonate-specific mechanism of hypothalamo-pituitary-adrenal-axis control.

In this study, we investigated the effect of chronic repeated restraint (RR) on prolactin‐releasing peptide (PrRP) expression. In the brainstem, where PrRP colocalize with norepinephrine in neurons of the A1 and A2 catecholaminergic cell groups, the expression of tyrosine hydroxylase (TH) has also been examined. In the brainstem, but not in the hypothalamus, the basal PrRP expression in female rats was higher than that in the males that was abolished by ovariectomy. RR evoked an elevation of PrRP expression in all areas investigated, with smaller reaction in the brainstems of females. There was no gender‐related difference in the RR‐evoked TH expression. Elevation of PrRP was relatively higher than elevation of TH, causing a shift in PrRP/TH ratio in the brainstem after RR. Estrogen α receptors were found in the PrRP neurons of the A1 and A2 cell groups, but not in the hypothalamus. Bilateral lesions of the hypothalamic paraventricular nucleus did not prevent RR‐evoked changes. Elevated PrRP production parallel with increased PrRP/TH ratio in A1/A2 neurons indicate that: (i) there is a clear difference in the regulation of TH and PrRP expression after RR, and (ii) among other factors this may also contribute to the changed sensitivity of the hypothalamo‐pituitary–adrenal axis during chronic stress.

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Zelena, Dóra, Ludmila Filaretova, Zsuzsa Mergl, István Barna, Zsuzsanna E. Tóth, and Gábor B. Makara. Hypothalamic paraventricular nucleus, but not vasopressin, participates in chronic hyperactivity of the HPA axis in diabetic rats. Am J Physiol Endocrinol Metab 290: E243-E250, 2006. First published September 6, 2005 doi:10.1152/ajpendo.00118.2005.-Diabetes mellitus (DM), as chronic stress activates the hypothalamopituitary-adrenocortical axis. We examined whether arginine vasopressin (AVP) and the hypothalamic paraventricular nucleus (PVN) participate in DM-induced chronic stress symptoms. AVP-deficient Brattleboro or PVN-lesioned Wistar rats were used with heterozygous or sham-operated controls. The rats were studied 2 wk after a single injection of streptozotocin. The appearance of DM (enhanced water consumption and blood glucose elevation) and the chronic stress-like somatic changes (body weight decrease, thymus involution, adrenal gland hypertrophy) were not influenced by the lack of AVP. By contrast, PVN lesion significantly attenuated DM-induced thymus involution and adrenal gland hypertrophy as well as the increase in water consumption. The corticotropin-releasing hormone mRNA in PVN was diminished by DM and elevated by the lack of AVP without interaction. DM elevated the proopiomelanocortin (POMC) mRNA in the anterior lobe of the pituitary. The lack of AVP had no effect, whereas lesioning the PVN significantly diminished the elevation. The elevated basal corticosterone plasma levels detectable in DM were influenced neither by the lack of AVP nor by lesioning the PVN. Thus the lack of AVP had no influence on DM-induced chronic stress symptoms, but lesioning the PVN attenuated part of them. However, the lack of elevation in POMC mRNA after PVN lesion, together with the maintained corticosterone elevation, suggests that direct adrenal gland activation occurs in untreated DM. chronic stress; Brattleboro rats; corticosterone; proopiomelanocortin; corticotropin-releasing hormone; diabetes mellitus; hypothalamopituitary-adrenocortical axis DIABETES MELLITUS (DM) is an endocrine disorder that is quite common in developed countries (17). Inadequate insulin secretion and insulin resistance with inadequate compensatory insulin release are the main reasons for DM development. The use of toxic agents that destroy ␤-cells in the pancreas and lead to insulin deficiency, such as streptozotocin (STZ), produces a model of DM in animals (36). The most frequent symptoms of DM are blood glucose level elevation, polyuria, polydipsia, and weight loss. However, the long-term disorder can cause many other complications, including cardiovascular, cerebrovascular, or renal ones.Long-term DM as a chronic stress may also induce a dysfunction of the hypothalamo-pituitary-adrenocortical (HPA) axis. A tight connection between HPA axis activity and blood glucose regulation is well known (9, 12). The HPA axis is responsible for the production of glucocorticoids, which are important adaptive hormones. Glucocorticoid hormones participate...

The hypothalamo-pituitary-adrenal (HPA) axis is a key component of the stress reaction. Most contemporary reviews mention the corticotropin-releasing hormone and arginine vasopressin (AVP)-containing parvocellular neurons of the hypothalamic paraventricular nucleus as the endocrinomotor component of the system. Although there are many studies about the role of AVP in the stress activation, there is evidence consistent and inconsistent with the general view on the importance of AVP. We propose a list of experiments that may provide critical evidence for or against the widely held opinion. The naturally AVP-deficient Brattleboro rat seems to be a good tool for studying the role of AVP. Our experiments on Brattleboro rats with restraint and ip hypertonic saline injection did not support the prominent role of AVP in acute stress, although in forced swim the lack of AVP influenced the HPA axis activation. Among different chronic stress situations (14 days' restraint, chronic morphine or ip hypertonic saline treatment, streptozotocin-induced diabetes mellitus), the role of AVP was not confirmed by changes in somatic parameter (i.e., body, thymus, and adrenal weight changes).

The role of vasopressin, cosecreted with corticotropin-releasing hormone (CRH), in stress is debated, because both normal as well as reduced adrenocorticotropin hormone (ACTH) rise to an acute challenge has been reported in Brattleboro rats genetically lacking vasopressin (di/di). Because di/di pups could be born either from di/+ (heterozygous) or from di/di mothers, and maternal influence is known to modify adult responsiveness, we investigated whether the influence of maternal genotype could explain the variability. Adult rats from mothers with different genotypes were stressed with 60 min restraint and trunk blood was collected for measuring hormone content by radioimmunoassay at the end of stress. All offspring of di/+ mothers had similar ACTH responses to restraint, while the di/di rats born to, and raised by di/di mothers showed reduced ACTH reactivity to restraint. The di/di rats showed elevated water turnover and required a daily cage cleaning every day, which meant frequent handling. To offset the role of handling, all rats had daily cage cleaning in the next series, but the results were the same as in the first series. To investigate whether lactation, the behaviour of the mother or some other factor during the pregnancy is responsible for the differences, pups from di/+ dams were raised by di/di foster mothers and vice versa. We found that the genotype of parental mother is more important than that of the foster mother. The corticosterone and prolactin elevation normally seen after acute stress was unchanged by family history, maternal or personal genotype. Furthermore, in studies with mutant animals, the rearing conditions should be controlled by the experimenter. In experiments with Brattleboro rats, the use of homozygous and heterozygous rats from the same litters of di/+ dams and di/di males is recommended. Our results suggest that vasopressin is not indispensable for ACTH release, and that the di/di genotype of the parental mother can decrease the stress reactivity of the di/di Brattleboro rats.