Corticotropin-releasing Hormone mRNA Expression Research Articles

Antidepressant-like effects of sodium butyrate in combination with estrogen in rat forced swimming test: Involvement of 5-HT 1A receptors

Sodium butyrate (NaB), a histone deacetylase inhibitor, has been implicated in the antidepressant-like effects either injected as a single drug or in combination with selective serotonin reuptake inhibitor (SSRI), such as fluoxetine. Estrogen is also demonstrated to have antidepressant effect especially together with fluoxetine. We investigated whether NaB administered in combination with estradiol benzoate (EB) exerted antidepressant-like effect in forced swimming test (FST) in ovariectomized female rats. Furthermore, we detected the mRNA expressions of serotonin receptors and neuropeptides in hypothalamus, both of which participate in the mood disorder. Ovariectomized female SD rats were treated with vehicle, NaB, EB or NaB combined with EB for 7 days and then subjected to FST. The expressions of serotonin receptors (5-hydroxytryptamine receptor), corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA in the hypothalamus were detected by real time PCR. We found that co-treated with NaB and EB resulted in a significant decrease in immobility behavior in FST, a measure for depression-like behavioral. 5-HT 1A antagonist, WAY 100635, significantly block the antidepressant-like effects induced by NaB plus EB. The mRNA expression of the serotonin-1A [5-hydroxytryptamine 1A (5-HT 1A)] receptor was increased in the co-treated group in hypothalamus, while there was no difference in the mRNA expression of 5-HT 2A or 5-HT 2C. The mRNA expression of CRH or AVP was not significantly altered either. In conclusion, NaB may exert antidepressant-like effects in combination with EB in ovariectomized female rats through 5-HT 1A receptor, via altering the expression of 5-HT 1A in the hypothalamus.

Expression of mRNA for corticotropin-releasing hormone and vasopressin in the hypothalamus and amygdala of rats after administration of narcogenic

Male Wistar rats received intraperitoneal injections of physiological saline (control), phenamine, fentanyl, ethanol, sodium ethaminal, or dexamethasone in increasing concentrations for 4 days. Forced administration of these drugs provided gradual load of the organism and prevented the development of tolerance. Such approach is extensively used for the development of drug addiction or several manifestations of this state. Expression of corticotropin-releasing hormone mRNA in the amygdala was maximum after administration of dexamethasone (0.46 arb. units vs. beta-actin), but was much lower in experiments with sodium ethaminal and fentanyl (0.07 and 0.037 arb. units, respectively). In the hypothalamus, enhanced mRNA expression was observed after injection of sodium ethaminal, ethanol, and fentanyl (0.8, 0.37, and 0.039 arb. units, respectively). Phenamine did not increase mRNA expression in the amygdala and hypothalamus. Expression of vasopressin mRNA was not detectable in brain structures of animals from various groups. Our results indicate that the hypothalamic reinforcement system provides a similar response to narcogens, whereas the extended amygdala includes elements of both reinforcement and stress reactivity.

Direct Inhibitory Effect of Glucocorticoids on Corticotrophin‐Releasing Hormone Gene Expression in Neurones of the Paraventricular Nucleus in Rat Hypothalamic Organotypic Cultures

Corticotrophin-releasing hormone (CRH) in the parvocellular neurosecretory neurones of hypothalamic paraventricular nucleus governs neuroendocrine stress cascade and is the major target of the negative feedback effect of corticosteroids. To assess whether glucocorticoids exert their inhibitory effect on CRH expression directly on parvocellular neurones or indirectly through a complex neuronal circuit, we examined the effect of corticosterone (CORT) and dexamethasone (DEX) on CRH mRNA levels in slice explant cultures of the rat hypothalamus. Organotypic slice cultures were prepared from 6 days old rat pups and maintained in vitro for 14 days. CRH mRNA expression was measured by in situ hybridisation histochemistry. Under basal conditions, CRH mRNA expressing cells were exclusively revealed in the paraventricular region along the third ventricle. Inhibition of action potential spike activity by tetrodotoxin (TTX, 1 microm) reduced CRH mRNA signal in the organotypic cultures. CORT (500 nm) or DEX (50 nm) treatment for 24 h significantly inhibited CRH expression in the parvocellular neurones and this effect of corticosteroids was not affected following blockade of voltage dependent sodium channels by TTX. Forskolin-stimulated CRH mRNA levels in the paraventricular nucleus were also inhibited by CORT or DEX in the presence and in the absence of TTX. These studies identify paraventricular CRH neurones as direct target of corticosteroid feedback. Type II corticosteroid receptor agonists act directly on paraventricular neurones to inhibit basal and forskolin-induced CRH mRNA expression in explant cultures of the rat hypothalamus.

CRH mRNA expression in the hypothalamic paraventricular nucleus is inhibited despite the activation of the hypothalamo-pituitary-adrenal axis during starvation

Corticotropin-releasing hormone (CRH) is one of the anorexigenic neuropeptides, and indeed the expression of hypothalamic CRH is known to be inhibited by starvation. To clarify whether elevated plasma glucocorticoid during starvation is responsible for the CRH suppression, we examined the expression level of hypothalamic CRH mRNA after food deprivation in adrenalectomized, plasma corticosterone (B)-clamped animals. Male Wistar rats were divided into 2 groups: one group had adrenalectomy (ADX) and B pellet implantation (ADX + B, n = 42), and the other group had only sham operation (sham, n = 42). Rats were then treated with either ad libitum food supply or food deprivation for up to 96 h. The expression of CRH mRNA in the paraventricular nucleus (PVN) was estimated by in situ hybridization. After food deprivation, mean plasma B level was markedly elevated in sham group, but almost clamped in the ADX + B group. In this experimental condition, CRH mRNA in the PVN was significantly decreased in the sham group, whereas no change was obtained in the ADX + B group. Our data suggest the decrease in CRH mRNA seems to be related to the elevated glucocorticoid level during starvation. The status of hyperadrenocorticism without activation of CRH led us to speculate that adrenocortical function is predominant in the hypothalamic-pituitary-adrenal (HPA) axis during starvation.

Consequences of chronic social stress on behaviour and vasopressin gene expression in the PVN of DBA/2OlaHsd mice—influence of treatment with the CRHR1-antagonist R121919/NBI 30775

Accumulating evidence suggests that corticotropin-releasing hormone (CRH) neurocircuitry modulate the neuroendocrine and behavioural phenotypes in depression and anxiety. Thus, the administration of the selective CRH-receptor 1 (CRHR1)-antagonist R121919/NBI 30775 has proven its ability to act as an anxiolytic in rats. It is still unclear whether vasopressinergic neuronal circuits, which are known to be involved in the regulation of emotionality, are affected by R121919/NBI 30775. Using DBA/2OlaHsd mice, we investigated the effects of chronic social defeat and concomitant treatment with R121919/NBI 30775 on 1) the behavioural profile in the modified hole board test and 2) in-situ hybridization analysis-based expression of arginine vasopressin (AVP) and CRH mRNA in both the hypothalamic paraventricular nucleus and supraoptic nucleus. The results suggest that chronic social defeat leads to increased avoidance behaviour and reduction in directed exploration, general exploration, and locomotion. Chronic treatment with the CRHR1-antagonist was effective in reversing the directed exploration to control level. The dissection of the antagonist-treated group into responders and non-responders using the parameter time spent on board revealed further positive effects of R121919/NBI 30775 on avoidance behaviour and locomotion. Behavioural changes were accompanied by alterations in AVP gene expression in the paraventricular nucleus. Taken together, the anxiolytic action of the CRHR1 antagonist was found in a subgroup of animals only, and further studies have to be done to clarify the inter-individual biological differences in response patterns to this compound to optimise its application under clinical conditions.

Dysfunctional nurturing behavior in rat dams with limited access to nesting material: A clinically relevant model for early-life stress

Background Early-life emotional stress may be associated with affective and cognitive disorders later in life, yet satisfactory animal models for studying the underlying mechanisms are limited. Because maternal presence and behavior critically influence molecular and behavioral stress responses in offspring, we sought to create a model of dysfunctional, fragmented maternal nurturing behavior that would, in turn, provoke chronic early-life stress in the offspring. Methods Sprague-Dawley rat dams' nursing and nurturing behaviors were altered by limiting their ability to create satisfactory nests during postpartum days 2–9. Maternal behavior was observed throughout the diurnal cycle, and the frequency and duration of nurturing behaviors were scored. In addition, potential stress and anxiety of the dams were assessed using behavioral, molecular and hormonal measures. Results Both the quantity and the quality of dams' care of their pups were profoundly influenced by restriction of nesting materials in their cages: licking/grooming activities decreased and the frequency of leaving the pups increased, resulting in fragmented interactions between the dams and pups. The abnormal activity patterns of the dams were accompanied by increased anxiety-like behavior in the open field, but not in the elevated plus maze tests. Additionally, dams' plasma corticosterone levels and adrenal weights were augmented, suggesting chronic stress of these dams. By the end of the limited-nesting, stress-inducing period, hypothalamic corticotropin releasing hormone (CRH) mRNA expression was reduced in the limited-nesting dams, while arginine-vasopressin (AVP) mRNA levels were not significantly affected. Conclusion Limiting dams' ability to construct a nest for their pups leads to an abnormal repertoire of nurturing behaviors, possibly as a result of chronic stress and mild anxiety of the dams. Because the fragmented and aberrant maternal behavior provoked chronic stress in the pups, the limited-nesting paradigm provides a useful tool for studying the mechanisms and consequences of such early-life stress experience in the offspring.

An estrogenic effect of 5α-androstane-3β, 17β-diol on the behavioral response to stress and on CRH regulation

The gender difference in behavioral and hormonal response to stress is well known, but the underlying mechanism remains elusive. Arginine-vasopressin (AVP) and corticotrophin-releasing hormone (CRH) are two major regulatory peptides in the brain involved in stress regulation. Their response to stress has been shown to be modulated by sex hormones. The androgen metabolite, 5α-androstane-3β, 17β-diol (3β-diol), has been identified as an estrogenic hormone. It binds to estrogen receptors (ERs) and modulates estrogen response element mediated promoter activities via the ER pathway. The present study involved in vitro transfection assays to examine whether 3β-diol can directly modulate CRH and AVP promoter activity. Our results demonstrate that in CHO-K1 cell lines, when ERs were over-expressed, 3β-diol could significantly stimulate CRH and AVP promoter activity through an ER pathway. The effect of 3β-diol on the behavioral, the CRH and the AVP response to stress in the rat was also investigated. We found that chronic, but not acute administration of 3β-diol significantly decreased the immobile duration in the forced swim test. In rats exposed to the forced swim test, CRH mRNA expression in the hypothalamus was enhanced by chronic 3β-diol administration, while the AVP mRNA expression was not affected. These results suggest that 3β-diol may play an anti-depressive role in affective behavior and may have a direct effect on CRH expression.

Interleukin-6 and the Hypothalamic-Pituitary-Adrenal Activation in a Tumor Bearing Mouse

Tumor derived cytokines have been suggested to activate the hypothalamic-pituitary-adrenal (HPA) axis; that is, increase the hypothalamic releases of corticotropin-releasing hormone (CRH) and adrenocorticotrophic hormone. The authors previously reported that tumor mice bearing a human oral squamous cell carcinoma exhibit an anorectic phenotype with increased expression of CRH mRNA in their hypothalamic paraventricular nuclei. This study examined the plasma levels of tumor-derived cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in order to determine potential mediator(s) implicated in CRH expression in this tumor mouse model. Plasma corticosterone levels were assayed as well to confirm the HPA activation. In the results, plasma levels of IL-6, but not TNF-α, were increased significantly in the tumor mice compared with age-matching non-tumor controls. Plasma corticosterone levels were also increased in the tumor mice. These results together with the previous findings suggest IL-6 as a potential mediator in the control of hypothalamic CRH expression in the authors’ tumor mouse model.

The role of corticotrophin-releasing hormone receptors in the calcitonin gene-related peptide-induced suppression of pulsatile luteinising hormone secretion in the female rat

Corticotrophin-releasing hormone (CRH) plays a pivotal role in the suppression of the gonadotrophin-releaning hormone (GRH) pulse generator in response to stress and intracerebroventricular (icv) administration of calcitonin gene-related peptide (CGRP). We have previously shown both CRH receptor subtypes, CRH-R1 and CRH-R2, are involved in the stress-induced suppression of LH pulses. The aims of the present study were to examine the role of CRH-R1 and CRH-R2 in CGRP-induced suppression of LH pulses, and to investigate the effects of CGRP on CRH expression in the paraventricular nucleus (PVN) and central nucleus of the amygdala (CeA), which have prominent CRH neurone populations that receive dense CGRP innervations. The suppression of LH pulses by CGRP (1.5 μg icv) was completely prevented by intravenous administration of the CRH-R1 antagonist SSR125543Q (7.5 mg/rat iv, 30 min before CGRP), but was not affected by the CRH-R2 antagonist, astressin2-B (100 μg icv, 10 min before CGRP). CGRP increased the CRH mRNA expression in PVN and CeA. These results provide evidence of a role for CRH-R1 in mediating the suppressive effects of CGRP on pulsatile LH secretion in the female rat, and additionally raise the possibility of an involvement of PVN and CeA CRH neuronal populations in this suppression.

Acute stress differentially affects corticotropin-releasing hormone mRNA expression in the central amygdala of the “depressed” flinders sensitive line and the control flinders resistant line rats

Preclinical and clinical evidence suggests that neuropeptides play a role in the pathophysiology of mood disorders. In the present study, we investigated the involvement of the peptides corticotropin-releasing hormone (CRH), neuropeptide Y (NPY) and nociceptin/orphanin FQ (N/OFQ) and of their receptors in the regulation of emotional behaviours. In situ hybridization experiments were performed in order to evaluate the mRNA expression levels of these neuropeptidergic systems in limbic and limbic-related brain regions of the Flinders Sensitive Line (FSL) rats, a putative genetic animal model of depression. The FSL and their controls, the Flinders Resistant Line (FRL) rats, were subjected to one hour acute restraint and the effects of the stress exposure, including possible strain specific changes on these neuropeptidergic systems, were studied. In basal conditions, no significant differences between FSL and FRL rats in the CRH mRNA expression were found, however an upregulation of the CRH mRNA hybridization signal was detected in the central amygdala of the stressed FRL, compared to the non stressed FRL rats, but not in the FSL, suggesting a hypoactive mechanism of response to stressful stimuli in the “depressed” FSL rats. Baseline levels of NPY and N/OFQ mRNA were lower in the FSL rats compared to the FRL in the dentate gyrus of hippocampus and in the medial amygdala, respectively. However, the exposure to stress induced a significant upregulation of the N/OFQ mRNA levels in the paraventricular thalamic nucleus, while in the same nucleus the N/OFQ receptor mRNA expression was higher in the FSL rats. In conclusion, selective alterations of the NPY and N/OFQ mRNA in limbic and limbic-related regions of the FSL rats, a putative animal model of depression, provide further support for the involvement of these neuropeptides in depressive disorders. Moreover, the lack of CRH activation following stress in the “depressed” FSL rats suggests a form of allostatic load, that could alter their interpretation of environmental stimuli and influence their behavioural response to stressful situations.

Effects of electro-acupuncture on hypothalamic-pituitary-adrenal index and corticotropin releasing hormone mRNA expression of rats with chronic fatigue syndrome

Objective To investigate the mechanism of electroacupuncturein treating chronic fatigue syndrome(CFS) in term of the neuro-endocrine system by observing the regulative effect of EA on hypothalamic-pituitary-adrenal index (HPA index) and corticotropin releasing hormone mRNA (CRH mRNA) in CFS model rats.

Bioactive compounds from Paecilomyces tenuipes regulating the function of the hypothalamo-hypophyseal system axis in chronic unpredictable stress rats

A bioactive compound from Paecilomyces tenuipes (BCPT) has an inhibitory effect on monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) in vitro and in vivo, which indicates BCPT may be a potential antidepressant. In this study we aimed to study the antidepressant effects of BCPT in the chronic unpredictable stress (CUS) model in rats and explore underlying mechanisms in the hypothalamic-pituitary-adrenal (HPA) axis. The antidepressant effects of BCPT were studied in the chronic unpredictable stress model in rats. Animals were housed isolated, except the control group. Rats were exposed daily to different random stressors from day 1 to 21. Awarding response was detected by calculating the 24-hour consumption of sucrose water. Cortisol (CORT) and adrenocorticotropic hormone (ATCH) contents in serum and arginine vasopressin (AVP) contents in the pituitary body were detected by radio immunoassays. Total RNA of hippocampus or hypothalamus was extracted and subjected to reverse transcription-polymerase chain reaction (RT-PCR) for the measurement of corticotrophin releasing hormone (CRH) mRNA or mineralocorticoid receptor (MR) mRNA and glucocorticoid receptor (GR) mRNA levels. Statistical analyses were performed using one way analysis of variance (ANOVA) followed by Student-Newman-Keuls (SNK) test. Chronic unpredictable stress resulted in reduction of sensitivity to reward and abnormality in the HPA axis in the animal model. BCPT improved the reward reaction as measured by increasing sucrose consumption, remarkably reduced serum CORT and ACTH levels and the AVP content in the pituitary body in the CUS-treated rats, decreased the expression of CRH mRNA, enhanced the expression of hippocampus MR mRNA, GR mRNA and decreased the ratio of MR/GR. BCPT has potentially antidepressant-like activity and normalized the HPA axis hyperactivity in a CUS model of depression in rats. This may be an important mechanism of its antidepressant effect.

Age- and Stress-Induced Changes in Corticotropin-Releasing Hormone mRNA Expression in the Paraventricular Nucleus of the Hypothalamus

In reaction to acute stress, prepubertal (25–28 days of age) animals demonstrate a prolonged adrenocorticotropic hormone (ACTH) and corticosterone response compared to adults (>65 days of age), while after chronic stress, prepubertal animals show a higher peak ACTH and corticosterone response, but a faster return to baseline compared to adults. Differential activation of corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) of prepubertal and adult animals have been suggested to mediate these changes in stress responsiveness. The purpose of the present set of experiments was to further elucidate possible differences in PVN structure and function in prepubertal (28 days of age) and adult (77 days of age) male rats. The results indicate that PVN volume and somal size and cell number are similar in the parvocellular and magnocellular subdivision of the PVN before and after pubertal development. Furthermore, after a peripheral injection of the retrograde tracer Fluoro-Gold (FG), prepubertal and adult males demonstrate similar numbers of anterior pituitary projecting neurosecretory neurons in the parvocellular region of the PVN. Finally, using in situ hybridization we show that in response to acute stress, CRH mRNA in the PVN was affected by both age and stress such that prepubertal males have greater CRH expression than adults and both prepubertal and adult males show significant stress-induced increases in CRH mRNA. Interestingly, in response to repeated restraint, neither age nor stress significantly influence CRH expression. Together, these data indicate that both age and experience with stress interact to modulate CRH expression in the PVN.

Prenatal high-salt diet in the Sprague-Dawley rat programs blood pressure and heart rate hyperresponsiveness to stress in adult female offspring

Several animal models have been developed to study fetal programming of hypertension. One model involves feeding high-salt (HS) diet to rats before and during pregnancy, during lactation, and after weaning for 10 days. In the present investigation, we limited HS diet to the prenatal period in an attempt to find a narrower critical window for fetal programming. The HS diet did not result in low-birth weight offspring. In the adult offspring, radiotelemetry was used to assess blood pressure and heart rate in the conscious unstressed state. As adults, the HS offspring were not hypertensive compared with normal-salt (NS) control animals. However, the pressor and tachycardic responses to 1-h of restraint were significantly enhanced in HS female offspring, and recovery after restraint was delayed. This was accompanied by an increase in relative expression of corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus during basal and stressed conditions. There was no augmented stress response or relative increase in CRH mRNA in adult HS male offspring. When challenged with 1 wk of 8% NaCl diet as adults, neither HS male nor female offspring exhibited salt sensitivity compared with NS groups. These data show that a high-salt diet limited to the prenatal period is not sufficient to program hypertension in adult offspring. However, this narrower critical period is sufficient to imprint a lasting hyperresponsiveness to stress, at least in adult female offspring. These data indicate that excessive maternal salt intake during pregnancy can adversely affect the cardiovascular health of adult offspring.

Oestrogenic Regulation of Pro‐Opiomelanocortin, Neuropeptide Y and Corticotrophin‐Releasing Hormone mRNAs in Mouse Hypothalamus

It is well documented that oestrogen suppresses food intake by an action at the hypothalamic level. Using in situ hybridisation, we studied the effect of castration (CX) and short-term administration of oestradiol (E2) in CX female mice for three neuropeptides involved in feeding behaviour: two anorexigenic peptides, (i) the pro-opiomelanocortin (POMC)-derived peptide alpha-melanocyte-stimulating hormone and (ii) corticotrophin-releasing hormone (CRH), and the orexigenic peptide, (iii) neuropeptide Y (NPY). POMC-expressing neurones were mostly laterally located in the arcuate nucleus. POMC mRNA expression was decreased following CX and a single injection of E2 induced an increase in mRNA levels at 12- and 24-h time intervals. In the parvocellular area of the paraventricular nucleus, CRH mRNA levels were similarly decreased after CX and completely restored to normal levels at 12 and 24 h following E2 injection. On the other hand, the levels of NPY mRNA expressed in neurones located in the inner zone of the arcuate nucleus were increased by CX and decreased to the levels observed in intact animals by E2 injection (3-24 h). The present data suggest that oestrogen might exert an anorexigenic action by stimulating POMC and CRH mRNA expression and decreasing NPY mRNA expression in the hypothalamus.

Prepro-TRH 178–199 inhibits histamine- or restraint stress-induced activation of corticotropin releasing hormone production in rat hypothalamus

Under restraint stress conditions, prepro-thyrotropin releasing hormone (TRH) 178–199 suppresses adrenocorticotropic hormone (ACTH) secretion from the rat pituitary, which indicates that prepro-TRH 178–199 is a candidate endogenous corticotropin releasing inhibitory factor (CRIF). Restraint stress also activates the release of hypothalamic neuronal histamine, which increases both the expression of CRH mRNA in the paraventricular nucleus (PVN) and plasma concentrations of ACTH. The aim of this study was to determine whether prepro-TRH 178–199 modulates histamine- or restraint stress-induced activation of corticotropin releasing hormone (CRH) in the rat hypothalamus. Infusion of prepro-TRH 178–199 into the third cerebroventricle (i3vt) at a dose of 6 μg/kg significantly decreased the amount of CRH in the PVN, as compared to vehicle-treated controls ( p < 0.05), but did not affect the CRH amount in other hypothalamic regions. Restraint stress increased the amount of CRH in the PVN and ventromedial hypothalamic nucleus (VMH), as compared to non-restrained controls ( p < 0.05); this was attenuated by pretreatment with i3vt infusion of prepro-TRH 178–199 ( p < 0.05). I3vt infusion of histamine (270 nmol/rat) suppressed cumulative food consumption over 24 h, increased plasma ACTH concentrations, and increased the content of CRH in the PVN, as compared to vehicle-treated controls ( p < 0.05 for each); these effects were attenuated by pretreatment with prepro-TRH 178–199 ( p < 0.05). These results suggest that prepro-TRH 178–199 may regulate ACTH secretion by affecting basal and histamine- or stress-induced synthesis and/or secretion of CRH and ACTH by modulating histaminergic input to the PVN and VMH.

Prenatal stress increases HPA axis activity and impairs maternal care in lactating female offspring: Implications for postpartum mood disorder

Early life stress is believed to constitute a risk factor for the development of mood disorders later in life. In the present study, we hypothesized that prenatal stress (PS) exerts long-lasting effects in female rat offspring, resulting in impaired adaptations to stress during lactation and, as such, may be a contributory factor to postpartum mood disorders. PS increased anxiety in adult virgin females compared with controls. During lactation, PS dams nursed significantly less and spent less time with pups compared with controls, whereas dams did not differ in pup retrieval or maternal aggression. HPA axis reactivity was elevated in response to a mild stressor in PS dams compared to their controls, but not in virgins, with the delta corticosterone response returning to the higher level seen in virgins. Moreover, corticotropin-releasing hormone (CRH) mRNA expression within the parvocellular region of the paraventricular nucleus (PVN) was increased in both virgins and dams exposed to PS compared with the relative controls, while the attenuation in expression in lactating controls was abolished following PS. In addition, arginine vasopressin (AVP) mRNA was increased in the parvocellular, but not magnocellular part of the PVN, in both PS-exposed virgins and lactating dams compared with their relative controls; although expression was also higher in controls during lactation compared with virgins. Thus, the present study demonstrates that exposure to PS results in long-lasting behavioural and neuroendocrine alterations in the female offspring, which are manifested during the lactation period. Furthermore, it implicates PS as a potential risk factor for the development of postpartum mood disorders, and that alterations in the HPA axis reactivity, at least partially, are involved.

Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs.

Limbic and cortical neurocircuits profoundly influence hypothalamic-pituitary-adrenal (HPA) axis responses to stress yet have little or no direct projections to the hypothalamic paraventricular nucleus (PVN). Numerous lines of evidence suggest that the bed nucleus of the stria terminalis (BST) is well positioned to relay limbic information to the PVN. The BST comprises multiple anatomically distinct nuclei, of which some are known to receive direct limbic and/or cortical input and to heavily innervate the PVN. Our studies test the hypothesis that subregions of the BST differentially regulate HPA axis responses to acute stress. Male Sprague Dawley rats received bilateral ibotenate lesions, targeting either the principal nucleus in the posterior BST or the dorsomedial/fusiform nuclei in the anteroventral BST. Posterior BST lesions elevated plasma ACTH and corticosterone in response to acute restraint stress, increased stress-induced PVN c-fos mRNA, and elevated PVN corticotropin-releasing hormone (CRH) and parvocellular arginine vasopressin (AVP) mRNA expression relative to sham-lesion animals. In contrast, anterior BST lesions attenuated the plasma corticosterone response and decreased c-fos mRNA induction in the PVN but did not affect CRH and parvocellular AVP mRNA expression in the PVN. These data suggest that posterior BST nuclei are involved in inhibition of the HPA axis, whereas the anteroventral BST nuclei are involved in HPA axis excitation. The results indicate that the BST contains functional subdomains that play different roles in integrating and processing limbic information in response to stress and further suggest that excitatory as well as inhibitory limbic information is funneled through these important cell groups.

Changes in the Expression of Corticotrophin‐Releasing Hormone, Mineralocorticoid Receptor and Glucocorticoid Receptor mRNAs in the Hypothalamic Paraventricular Nucleus Induced by Fornix Transection and Adrenalectomy

The paraventricular nucleus (PVN) in the hypothalamus receives inputs from the hippocampus The present study explored the influence of the hippocampus on genes mediating glucocorticoid feedback in the PVN. Accordingly, the expression of mRNAs for corticotrophin-releasing hormone (CRH), the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) in the PVN was examined by in situ hybridisation in rats subjected to transection of the fornix. Significant increases in CRH, MR and GR mRNAs were observed in the parvocellular PVN after fornix transection (FT). FT-animals subjected to adrenalectomy also showed an increase in the number of cells positive for CRH and GR mRNAs. CRH, MR and GR mRNA expression was also increased by bilateral adrenalectomy, and GR mRNA expression was further enhanced in the parvocellular PVN of the FT transected animals. However, no such changes were evident in the magnocellular PVN. These results suggest that the input from the hippocampus to the PVN, particularly to its parvocellular region, has distinct and differential inhibitory effects on the expression of MR,GR and CRH mRNAs that may operate independently from the feedback actions of corticosterone.

Restraint-induced corticosterone secretion and hypothalamic CRH mRNA expression are augmented during acute withdrawal from chronic cocaine administration

Stress responses during cocaine withdrawal likely contribute to drug relapse and may be intensified as a consequence of prior cocaine use. The present study examined changes in stressor-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis during acute withdrawal from chronic cocaine administration. Adult male Sprague–Dawley rats received daily administration of cocaine (30 mg/kg, i.p.) or saline for 14 days. Twenty-four hours after the last injection, rats in each group were sacrificed under stress-free conditions or following 30 min of immobilization. Plasma corticosterone (CORT) was measured in trunk-blood using radioimmunoassay, corticotropin-releasing hormone (CRH) mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus were measured using in situ hybridization and glucocorticoid receptor (GR) protein expression in the pituitary gland and dissected brain regions was measured using Western blot analysis. Basal CRH mRNA in the PVN was unaltered as a result of prior cocaine administration. However, a significant increase in CRH mRNA was observed 90 min following the termination of restraint in cocaine withdrawn, but not saline-treated, rats. Basal CORT was also unaffected by prior cocaine administration, but the CORT response measured immediately after restraint was significantly augmented in cocaine-withdrawn rats. Differences in GR protein expression in number of regions implicated in negative feedback regulation of HPA function, including the hypothalamus, were not observed. These findings indicate that the HPA response to stressors is intensified during early withdrawal from cocaine administration and may be independent of changes in GR-mediated negative feedback.