[Sepsis-associated Purpura Fulminans International Registry--Europe (SAPFIRE)]. / Ein europäisches Register für sepsisassoziierte Purpura fulminans (SAPFIRE).

BACKGROUND: Purpura fulminans is a rare life-threatening condition which is characterized by disseminated thrombosis in dermal and systemic microcirculation, cutaneous hemorrhages with progressing necrosis and multiple organ failure. The underlying pathogenesis is based on the disruption of the intrinsic anticoagulation cascade, with protein C deficiency being considered the leading factor in this process. In the majority of cases, the condition emerges as consumptive coagulopathy associated with severe sepsis. OBJECTIVES: Epidemiological data on sepsis-associated purpura fulminans (SAPF) are scarce and evidence-based treatment guidelines have not been established yet. While restoration of the balance in the coagulation cascade is a declared therapeutic goal, evaluations of the efficacy of different therapeutic approaches in randomized clinical trials are still lacking. The causal role of individual microbial pathogens also requires comprehensive evaluation. METHODS: A prospective multicenter Sepsis-Associated Purpura Fulminans International Registry-Europe (SAPFIRE) will be established in the first quarter of 2015. For the first time, participating centers will systematically collect information on etiology, clinical course, biomarkers, treatment, morbidity, and mortality of SAPF. RESULTS: The SAPFIRE data will be periodically evaluated and disseminated. Retrospective analysis of each center's data and regular access to aggregated information collected by other centers will enable the participants to monitor and update care quality standards.

Telemetric assessment of referred vaginal hyperalgesia and the effect of indomethacin in a rat model of endometriosis.

Symptoms of endometriosis (ENDO), among others, include pelvic/abdominal and muscle pain. Non-steroidal anti-inflammatory agents are first-line treatment for this pain. Similar to women, rats with surgically induced ENDO, but not its surgical control, exhibit vaginal hyperalgesia, which in rats is evidenced by a decreased threshold for the visceromotor response (VMR) induced by vaginal distention. Here we assess the VMR in rats with implanted probes that telemetrically transmit EMG activity from the abdominal muscle. The feasibility and sensitivity of this technique for monitoring the VMR threshold across the estrous cycle and the influence of Indomethacin on ENDO-induced vaginal hyperalgesia were evaluated. VMR thresholds in response to vaginal distention with an infusion pump were measured in different estrous stages. Indomethacin (5 or 10 mg/kg i.p. or s.c.) was injected in proestrus rats and 40-60 min later the VMR threshold was measured. The VMR threshold varied across the estrous cycle only in ENDO rats, being lowest in proestrus. Indomethacin increased this threshold in proestrus ENDO rats. These results show that telemetric assessment of the VMR is a sensitive tool, suitable for long-term studies in conscious rats. The results with this technique also suggest that ENDO-associated vaginal hyperalgesia involves COX activity, the feature that also underlies inflammatory pains.

The role of Eralpha and ERbeta in the prostate: insights from genetic models and isoform-selective ligands.

Androgens are known regulators of the growth and differentiation of the prostate gland and are effective during development and maturity as well as in disease. The role of estrogens is less well characterized, but dual direct and indirect actions on prostate growth and differentiation have been demonstrated, facilitated via both ERalpha, and ERbeta. Previous studies using animal models to determine the role of ERbeta in the prostate have been problematic due to the centrally mediated responses to estrogen administration via ERalpha that can lower androgen levels and lead to epithelial regression, thereby masking any direct effects on the prostate mediated by ERbeta. Our alternate approach was to use the estrogen-deficient aromatase knockout (ArKO) mouse and the method of tissue recombination to provide new insight into estrogen action on prostate growth and pathology. Firstly, utilizing homo- and heterotypic tissue recombinants, we demonstrate that stromal aromatase deficiency results in the induction of hyperplasia in previously normal prostatic epithelium and that this response is the result of local changes to the paracrine interaction between stroma and epithelium. Secondly, using tissue recombination and an ERbeta-specific agonist, we demonstrate that the activation of ERbeta results in an anti-proliferative response that is not influenced by alterations to systemic androgen levels or activation of ERalpha. Finally, using intact ArKO mice this study demonstrates that the administration of an ERbeta-specific agonist abrogates existing hyperplastic epithelial pathology specifically in the prostate but an ERbeta-specific agonist does not. Therefore, in the absence of stromal aromatase gene expression, epithelial proliferation, leading to prostatic hypertrophy and hyperplasia, may result from a combination of androgenic stimulation of proliferation and failed activation of ERbeta by locally synthesized estrogens. These data demonstrate essential and beneficial effects of estrogens that are necessary for normal growth of the prostate and distinguish them from those that adversely alter prostate growth and differentiation. This indicates the potential of antiandrogens and SERMS, as opposed to aromatase inhibitors, for the management of prostate hyperplasia and hypertrophy.

Gender differences in the regulation of 3 alpha-hydroxysteroid dehydrogenase in rat brain and sensitivity to neurosteroid-mediated stress protection.

The enzyme 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) is involved in the generation of neuroactive steroids through ring-A-reduction of hormonal precursors. We examined the developmental regulation of, gender differences in, and effects of hormonal manipulations on the expression of 3 alpha-HSD in the rat hippocampus. High levels of 3 alpha-HSD mRNA were found on postnatal day 7, coinciding with the stress hyporesponsive period in the rat. Gender differences in 3 alpha-HSD expression were documented during puberty, but not in adulthood. Adrenalectomy and gonadectomy, and supplementation with individual steroid hormones influenced 3 alpha-HSD expression in a gender-specific mode. We also demonstrate that the manifestation of behavioral and endocrine consequences of early life stress depends on the individual's gender and gonadal status. Males are liable to aftereffects of neonatal maternal deprivation, regardless of their adult gonadal status. In females, however, anxiogenic aftereffects of neonatal stress become apparent only after gonadectomy. These data suggest that (i) transient increase of neurosteroid biosynthesis may contribute to stress hyporesponsiveness during early infancy; (ii) gonadal steroids regulate 3 alpha-HSD expression in the hippocampus in a sex-specific mode; (iii) physiological sex steroid secretions in females may mask behavioral consequences of adverse early life events, and (iv) concomitant treatment with the neurosteroid THP counteracts behavioral and endocrine dysregulation induced by neonatal stress in both genders.

17 Alpha-oestradiol and 17 beta-oestradiol do not affect basal and follicle-stimulating hormone-stimulated inhibin B secretion by highly purified rat Sertoli cells.

The effects of 17 alpha-oestradiol and 17 beta-oestradiol on basal and follicle-stimulating hormone (FSH)-stimulated inhibin B secretion by rat Sertoli cells were studied. Sertoli cells were isolated and cultivated from testes of 18-day-old Wistar rats in the presence and absence of FSH and different doses of oestrogens. On day 4 of culture, secreted inhibin was measured by enzyme-linked immunosorbent assay. Neither 17 alpha-oestradiol nor 17 beta-oestradiol had any effect on the secreted inhibin level in either the presence or absence of FSH. It is concluded that these oestradiols do not play an essential role in regulatory processes involving inhibin or FSH.

Plasticity of hippocampal corticosteroid receptors during aging in the rat.

Aging is commonly associated with dysregulation of the hypothalamo-pituitary-adrenal axis and cognitive impairment. On the basis of suggestions that these disruptions ensue from changes in the hippocampal complement of corticosteroid (mineralocorticoid and glucocorticoid) receptors (MR and GR), we examined the availability of hippocampal MR and GR by measuring the in vivo uptake of 3H-aldosterone and 3H-dexamethasone (selective MR and GR agonists, respectively); MR and GR mRNA levels were also measured. We observed age-related declines in both the synthesis of MR and GR and the uptake of their respective ligands. Whereas MR mRNA levels and ligand uptake declined in parallel, GR binding declined more steeply than GR mRNA. This latter result, together with our finding that aged rats show impaired corticosteroid receptor mRNA and protein up-regulation after corticosteroid withdrawal, indicates decreased transcription of MR and GR genes and posttranslational modification of GR mRNA during aging. Given that corticosteroids can influence MR and GR synthesis and binding, and based on the finding that aged subjects show reduced basal secretion of corticosterone, we propose that this relative hypocorticalism may be responsible for the changes observed in MR and GR activity, which then leads to disturbances in neuroendocrine regulation and cognitive function in aged subjects.

Ontogeny of gender-specific responsiveness to stress and glucocorticoids in the rat and its determination by the neonatal gonadal steroid environment.

The neuroendocrine response to stress in the rat displays gender-specific characteristics resulting from both sex hormone-dependent organization of neuroendocrine regulatory mechanisms and the modulatory action of circulating gonadal steroids. To define the role of gonadal steroid-mediated brain differentiation in the emergence of sex-specific differences in pituitary-adrenal function, and the necessity of physiological gonadal secretions for the manifestation of these differences, we examined the ontogeny of diurnal and stress-induced corticosterone (B) secretion, and suppressibility of the latter by dexamethasone (DEX) in intact male and female rats, and in animals that were subject to neonatal manipulations of the gonadal steroid environment (orchidectomy in males and neonatal estrogenization in females). Further, gene expression of corticosteroid receptors (MR and GR), corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) under basal conditions, and following adrenalectomy (ADX) and chronic supplementation with high doses of B, were investigated in adult male and female rats, and individuals of both sexes which have been exposed to alterations of the gonadal steroid milieu during early development. The results demonstrate that: i) gender-specific differences in basal and stress-induced adrenocortical secretion are present at birth, but are still maleable by neonatal alterations of the gonadal steroid environment; ii) gender-specific dichotomy in the sensitivity of the secretory stress response to glucocorticoid feedback becomes fully manifest in adulthood; iii) sex differences in basal adrenocortical secretion become fully expressed only in the presence of intact gonads, whereas, once established by the neonatal hormonal milieu, differential sensitivity of the stress response to glucocorticoids persists in the absence of functioning gonads; iv) neonatal hormone manipulations alter sex-specific characteristics of CRH, AVP, MR and GR gene expression in the brain, and the changes persist in adulthood independently of gonadal secretions; v) regulation of CRH gene expression by glucocorticoids displays gender-specific patterns which are probably established during the period of sex hormone-dependent brain organization and their manifestation does not require physiological gonadal secretions in adulthood.

Chronic melatonin treatment counteracts glucocorticoid-induced dysregulation of the hypothalamic-pituitary-adrenal axis in the rat.

Transient exposure of rats to high doses of dexamethasone (DEX; 500 microg/day for 5 days) produced a host of symptoms that are indicative of hypothalamic-pituitary-adrenal (HPA) axis dysregulation, such as increased adrenocortical secretion over 24 h, blunted and prolonged secretory response to emotional stress, refractoriness of adrenocorticotropin in vitro release to stimulation with the secretagogues corticotropin-releasing hormone (CRH) and vasopressin, decreased levels of mRNA encoding type II corticosteroid receptors in the hippocampus and increased numbers of transcripts encoding CRH in the paraventricular nucleus. Daily administration of melatonin (MEL; 80 microg/kg) concomitantly with, and for 5 days after discontinuation of, glucocorticoid treatment 'normalized' most of the symptoms of impaired HPA regulation caused by the exposure to DEX. While none of the treatments used caused major shifts in circadian patterns of corticosterone secretion, MEL administration was associated with diminished overall corticosterone secretion and increased sensitivity to glucocorticoid feedback. Taken together, these findings indicate that chronic MEL treatment may protect several regulatory components of the HPA axis from glucocorticoid-induced deterioration.

Gender differences in ethanol preference and ingestion in rats. The role of the gonadal steroid environment.

An ethanol oral self administration paradigm showed the existence of gender differences in alcohol preference in rats: whereas males and females initiated alcohol drinking at similar rates, females maintained their preference for ethanol over a longer duration. Neonatal estrogenization of females, which effectively confers a male phenotype on a genetically female brain, resulted in patterns of drinking that were similar to those displayed by intact male rats, indicating that gender differences in alcohol drinking patterns may be, at least partially, accounted for by sexual differentiation of the brain. To test whether gonadal steroids also exert activational effects on ethanol-seeking behavior, we also examined the effects of gonadectomy alone, or in combination with gonadal steroid replacement therapy. Castration did not significantly alter ethanol consumption in males, although treatment of castrated rats with dihydrotestosterone resulted in a significant inhibition of this parameter. As compared with the situation in intact female rats, ethanol ingestion was significantly reduced in ovariectomized female rats receiving estradiol (E2) and in ovariectomized female rats receiving combined E2 and progesterone replacement therapy. However, neither ovariectomy nor progesterone replacement in ovariectomized rats resulted in ethanol drinking patterns that were different compared to those observed in intact female controls. Thus, dihydrotestosterone and E2, respectively, appear to exert modulatory influences on the male and female rats' preference for ethanol, but further investigations are necessary to determine to what extent these effects result from activational actions on the brain.

Gender specificity in the neural regulation of the response to stress: new leads from classical paradigms.

Pronounced gender-related differences are observable in the regulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) activity under basal and stress-related conditions, and by circulating glucocorticoid levels. This article reviews recent studies that have unequivocally demonstrated that these differences emerge from the organizational effects of gonadal steroids during early brain development. Although largely masked by the dominating role of glucocorticoids in maintaining feedback thresholds, gonadal steroids continue to exert gender-specific activational effects on the LHPA axis through adulthood. The importance of these modulatory effects of gonadal steroids may be reflected in gender differences in the incidence of psychopathologies that are accompanied by symptoms of LHPA dysregulation. One goal of this review is to highlight the need for further investigations into the (still elusive) cellular and molecular mechanisms underlying the activational effects of sex steroids, which may provide leads for neuroprotective hormone replacement strategies.

Neonatal treatment of rats with the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) abolishes the behavioral and neuroendocrine consequences of adverse early life events.

Stressful experience during early brain development has been shown to produce profound alterations in several mechanisms of adaptation, while several signs of behavioral and neuroendocrine impairment resulting from neonatal exposure to stress resemble symptoms of dysregulation associated with major depression. This study demonstrates that when applied concomitantly with the stressful challenge, the steroid GABA(A) receptor agonist 3,21-dihydropregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) can attenuate the behavioral and neuroendocrine consequences of repeated maternal separation during early life, e.g., increased anxiety, an exaggerated adrenocortical secretory response to stress, impaired responsiveness to glucocorticoid feedback, and altered transcription of the genes encoding corticotropin-releasing hormone (CRH) in the hypothalamus and glucocorticoid receptors in the hippocampus. These data indicate that neuroactive steroid derivatives with GABA-agonistic properties may exert persisting stress-protective effects in the developing brain, and may form the basis for therapeutic agents which have the potential to prevent mental disorders resulting from adverse experience during neonatal life.

Activational effects of gonadal steroids on hypothalamo-pituitary-adrenal regulation in the rat disclosed by response to dexamethasone suppression.

Previous studies demonstrated that gonadal steroids secreted during perinatal life permanently 'organize' the mechanisms governing hypothalamo-pituitary-adrenal (HPA) function, leading to sexually differentiated patterns of pituitary-adrenal activity under basal and stress conditions. In this paper, we show that gonadal steroids can also exert 'activational' effects upon the HPA system. Examination of the ability of different doses of dexamethasone to suppress the nocturnal increase in corticosterone secretion and to attenuate the gene expression of CRH in the hypothalamic paraventricular nucleus of intact and gonadectomized male and female rats revealed that ovarian steroids make an important contribution to the higher sensitivity of the pituitary-adrenal axis in females to glucocorticoid suppression, whereas testicular steroids may be causal to the male's moderate responsiveness to glucocorticoid feedback. These findings may be implicated in a number of psychiatric and neurological disease states commonly associated with impaired HPA regulation, but which may be primarily rooted in altered gonadal steroid secretion.

Chronic melatonin treatment and the hypothalamo-pituitary-adrenal axis in the rat: attenuation of the secretory response to stress and effects on hypothalamic neuropeptide content and release.

The pituitary-adrenal secretory response to acute and chronic stress, suppressibility of adrenocortical secretions by exogenous glucocorticoids, and hypothalamic content and in vitro release of the two major peptidergic activators of the hypothalamo-pituitary-adrenal (HPA) axis, corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP), were examined in rats receiving daily melatonin (MEL) injections coincident with the circadian increment of endogenous pineal and adrenocortical secretory activity. After 7 days of MEL administration, the rats displayed a significant attenuation of the adrenocortical secretory response to acute and chronic stress. Chronic MEL treatment also prevented the decline in adrenocorticotropic hormone (ACTH) release resulting from chronic stress exposure. Hypothalamic CRH content was significantly lower in rats receiving MEL treatment, while AVP remained largely unaltered; however, MEL administration counteracted the chronic stress-induced decrease in hypothalamic AVP content and in vitro release. When exposed to dexamethasone in vitro, hypothalamic explants from MEL-treated rats responded with a stronger suppression of CRH and AVP release than those originating from vehicle-injected animals. These observations indicate that MEL attenuates the adrenocortical response to stress and influences the biosynthesis, release and glucocorticoid responsiveness of hypothalamic ACTH secretagogues.

The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus.

The neurosteroid tetrahydroprogesterone (5 alpha-pregnan-3 alpha-ol-20-one, allopregnanolone, THP), has been previously shown to counteract the anxiogenic effects of corticotropin-releasing hormone (CRH) and to interfere with noradrenergic and corticosteroid-mediated regulation of CRH release and gene transcription. Those observations indicated that, besides its sedative and analgesic activity, THP may also affect the neuroendocrine response to stress in a mode resembling that of corticosteroids. To examine this possibility, we compared the ability of THP, its precursor progesterone (P4), and the glucocorticoids dexamethasone (DEX) and corticosterone (CORT) to influence the pituitary-adrenal response to acute emotional stress and the adrenalectomy-induced increase in the gene transcription of the stress-related peptide arginine vasopressin (AVP) and of corticosteroid receptors (MR and GR) in the brain. Pretreatment of rats with a single dose of THP or P4 (50 micrograms/kg) significantly attenuated the elevation of plasma adrenocorticotropin (ACTH) and serum corticosterone after emotional stress; both steroids were, however, less potent than a similar dose of DEX. Administration of 1 mg of THP, CORT, or P4 to adrenalectomized (ADX) rats attenuated the increase in AVP mRNA levels in the ventromedial subdivision of the hypothalamic paraventricular nucleus (PVN), as compared with vehicle-treated ADX rats. However, whereas CORT and P4 influenced the ADX-induced increase in the transcription of both types of corticosteroid receptors in the hippocampus, these were unaffected by THP. In contrast to the glucocorticoids, THP and P4 failed to decrease plasma ACTH levels in rats deprived of endogenous steroids. These results demonstrate that the neurosteroid THP and its precursor P4 resemble glucocorticoids in their suppression of the pituitary-adrenal response to emotional stress; however, THP influences the transcription of glucocorticoid-responsive genes in brain structures involved in the regulation of the hypothalamo-pituitary-adrenal system in a fashion that is quite distinct from that obtained with glucocorticoids.

Gonadal steroids exert facilitating and "buffering" effects on glucocorticoid-mediated transcriptional regulation of corticotropin-releasing hormone and corticosteroid receptor genes in rat brain.

Gonadal steroids profoundly influence several brain functions and are apparently responsible for gender-specific differences in the regulation of hypothalamic-pituitary-adrenal (HPA) secretions. In this study, we examined the so-called "activational" effects of gonadal steroids on the glucocorticoid-mediated regulation of the gene transcription of corticotropin-releasing hormone (CRH) and corticosteroid receptors in brain areas of relevance for the control of pituitary-adrenal secretion. The efficacy of adrenalectomy (ADX) and chronic treatment with high doses of corticosterone (B) to regulate the gene transcription of CRH and corticosteroid receptors in the hypothalamic paraventricular nucleus (PVN) and hippocampus was studied in male and female rats under the conditions of deprivation of gonadectomy (GDX) and replacement with different gonadal steroids, such as estradiol (E2), progesterone (P), and dihydrotestosterone (DHT). In both sexes, ADX alone or in combination with GDX increased, and B treatment suppressed, the steady-state levels of CRH and corticosteroid receptor mRNAs, whereas GDX alone failed to affect any of the parameters studied. Administration of gonadal hormones to steroid-deprived (ADX/GDX) animals partially attenuated the upregulation of mRNAs encoding corticosteroid receptors in the hippocampus. Supplementation with gonadal steroids modified the effects of B on the gene transcription of CRH and corticosteroid receptors. Whereas P alone or in combination with E2 counteracted the B-induced downregulation of GR and CRH gene transcription in females, DHT and E2 administration further potentiated the effects of B on these parameters in a sex-specific manner. Taken together, the results indicate that gonadal steroids have minor influence on MR, GR, and CRH gene transcription under basal conditions, exert "glucocorticoid-like" effects on the transcription of corticosteroid receptors in the hippocampus of steroid-deprived animals, and interact with glucocorticoid-mediated mechanisms of regulation in the HPA axis through gender-specific "buffering" and "potentiating" effects.

Exacerbation of apoptosis in the dentate gyrus of the aged rat by dexamethasone and the protective role of corticosterone.

Glucocorticoid-induced cell loss in the dentate gyrus of rats of various ages was studied using the TUNEL procedure to detect apoptotic cells. A highly significant increase in the incidence of apoptosis was observed within the dentate hilus and granule cell layer within 24 h of a single injection of dexamethasone (DEX) in rats aged between 1 and 36 months; DEX-induced apoptosis was more pronounced with increasing age. Corticosterone (CORT) did not cause an increase in the rate of apoptosis above that found in age-matched controls. However, CORT pretreatment (3 h) resulted in a significantly attenuated DEX-induced apoptosis in both areas of the dentate gyrus. Serum CORT levels in saline-treated rats peaked at 6 months of age and reached a nadir at 36 months of age. The results indicate that (i) aged subjects are more susceptible to DEX in terms of dentate gyrus cell loss by apoptosis, (ii) CORT, which binds to Type I corticosteroid receptors with a high affinity, might serve to protect against the damaging effects of DEX which is a ligand of the Type II glucocorticoid receptor, and (iii) declining endogenous levels of CORT may increase the vulnerability of the dentate gyrus of aged rats to insult by DEX.

Regulation of rat mineralocorticoid receptor expression in neurons by progesterone.

We have studied the effects of progesterone on the transcription of the mineralocorticoid receptor (MR) gene in neurons in vitro and in vivo. Progesterone treatment caused a 2.5-fold increase in activity of the MR promoter in transiently transfected N2A neuroblastoma cells. Similarly, MR promoter activity in GH3 pituitary cells was increased 2-fold after treatment with the specific progesterone receptor agonist R5020, with an even greater induction after priming with 17 beta-estradiol. Progesterone treatment also produced a dose-dependent increase in MR messenger RNA (mRNA) levels in primary hippocampal neuron cultures. In vivo, chronic administration of progesterone to estrogen-primed adrenalectomized/ovariectomized rats significantly increased MR mRNA levels in all hippocampal subfields, as determined by semiquantitative in situ hybridization histochemistry. Whereas chronic estradiol treatment decreased MR mRNA levels in the hippocampus, progesterone administration in the absence of estradiol priming was without any effect. These results indicate that 1) progesterone increases MR mRNA levels in vitro and in vivo; 2) the stimulatory effects of progesterone are at least partially mediated by induction of MR promoter activity; and 3) estrogen priming is essential for the effect of progesterone upon MR mRNA in vivo. Further, they suggest the possibility of heterologous regulation of corticosteroid receptors in the brain, whereby the responsiveness of the limbic-hypothalamo-pituitary-adrenal system to corticosteroids may be modulated.

Lactation as a model for naturally reversible hypercorticalism plasticity in the mechanisms governing hypothalamo-pituitary- adrenocortical activity in rats.

Steady state levels of hypothalamic expression of the genes encoding corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), arginine vasopressin (AVP), and oxytocin (OT) were studied in rats to investigate the mechanisms underlying the transitions between hypercorticalism during lactation and normocorticalism upon weaning. During lactation, CRH mRNA levels and blood titers of adrenocorticotropin (ACTH) were found to be significantly reduced, although POMC mRNA levels in the anterior pituitary were not significantly different from those found in cycling virgin (control) rats; during all phases of lactation, an inverse relationship was observed between the blood levels of ACTH and corticosterone (CORT). Plasma prolactin (PRL) concentrations were elevated approximately 30-fold during lactation. Whereas steady state levels of OT mRNA were markedly increased throughout lactation, those of AVP mRNA were only transiently (initially) elevated, and the blood levels of these hormones were not significantly altered in lactating as compared with cycling virgin and postlactating rats. CRH and POMC gene expression and blood levels of ACTH, CORT, and PRL were normalized within 1-3 d of removal of suckling pups. The temporal relationships between the biosynthetic profiles of the various peptide hormones and the patterns of ACTH and CORT secretion during the two physiological states suggest that lactation-associated hypercorticalism does not merely result from increased ACTH secretion; although still not well substantiated at this time, the evidence points to contributory roles of PRL, OT, and AVP in the hypercorticalismic state found during lactation.

Corticosteroid regulation of gene expression and binding characteristics of vasopressin receptors in the rat brain.

Arginine-vasopressin (AVP) plays significant roles in neuroendocrine and autonomic regulation, and in processing of cognitive information. Its synthesis and secretion are subject to control by circulating glucocorticoids. The lateral septum and subdivisions of the hippocampus are innervated by AVP-ergic fibres and, together with AVP-producing neurons in the hypothalamic paraventricular nucleus, are major neural targets of glucocorticoid negative feedback. In this study, we investigated the effects of chronic adrenalectomy (ADX) and subsequent treatment with supraphysiological doses of corticosterone (B) on the gene expression of AVP receptors of the V1a subtype in the septum, hippocampus and hypothalamic arcuate (ARC) nucleus using semiquantitative in situ hybridization histochemistry. Adrenalectomy did not alter AVP receptor expression in any of the structures studied. Supplementation with B significantly decreased AVP receptor expression in the lateral septum and hippocampus, whereas receptor mRNA levels in the ARC were indistinguishable from those measured in controls. In a complementary study, we investigated the binding characteristics of V1 AVP receptors in membrane preparations from the hippocampus. Adrenalectomy significantly decreased the number of AVP binding sites, and chronic corticosteroid treatment was associated with a further suppression of AVP receptor concentrations in this structure. These results indicate that the gene transcription of V1a AVP receptors in the brain is regulated by circulating glucocorticoids in a site-specific fashion that largely reflects the corticosteroid sensitivity of the corresponding structure.(ABSTRACT TRUNCATED AT 250 WORDS)

Differences in arylalkylamine N-acetyltransferase activity between inflammatory disease-susceptible Lewis and -resistant Fischer rats.

Lewis (LEW/N) and Fischer (F344/N) rats are histocompatible inbred strains characterized, respectively, by susceptibility and resistance to inflammatory disease. The susceptibility of LEW/N rats to inflammation has been associated with deficient corticotropin-releasing hormone (CRH), ACTH, and corticosterone responses to inflammatory stimuli, specifically attributed to a global impairment in hypothalamic CRH neuron function. In contrast to the LEW/N rats, F344/N rats demonstrate an intact hypothalamic-pituitary-adrenal (HPA) axis. Melatonin, a neurohormone initially isolated in the pineal gland, has been implicated with inhibition of the HPA axis. To investigate melatonin synthesis and secretion in LEW/N and F344/N rats, we examined the diurnal activity of pineal arylalkylamine N-acetyltransferase (NAT1), the rate-limiting enzyme in melatonin biosynthesis, which demonstrates circadian rhythmicity, as well as the diurnal levels of serum melatonin, in both strains. Arylamine N-acetyltransferase (NAT2), a related enzyme activity, thought not to be regulated in a circadian manner, was examined as a control of NAT1 activity. Pineal NAT1 activity peak was observed later and reached significantly higher levels in LEW/N than in F344/N rats. Serum melatonin levels reflected the circadian pattern of the NAT1 activity, without, however, showing any quantitative differences between the two strains. Time-course of pineal NAT1 activity response to beta-adrenergic stimulation was parallel in the two rat strains, whereas the magnitude of the response as greater in LEW/N than in F344/N rats. No circadian or major quantitative differences in NAT2 activity were found between the two strains. Size-exclusion HPLC chromatograms of NAT1 activity revealed similar patterns in both rat strains.(ABSTRACT TRUNCATED AT 250 WORDS)