Endocannabinoids gate state-dependent plasticity of synaptic inhibition in feeding circuits.

Changes in food availability alter the output of hypothalamic nuclei that underlie energy homeostasis. Here, we asked whether food deprivation impacts the ability of GABA synapses in the dorsomedial hypothalamus (DMH), an important integrator of satiety signals, to undergo activity-dependent changes. GABA synapses in DMH slices from satiated rats exhibit endocannabinoid-mediated long-term depression (LTD(GABA)) in response to high-frequency stimulation of afferents. When CB1Rs are blocked, however, the same stimulation elicits long-term potentiation (LTP(GABA)), which manifests presynaptically and requires heterosynaptic recruitment of NMDARs and nitric oxide (NO). Interestingly, NO signaling is required for eCB-mediated LTD(GABA). Twenty-four hour food deprivation results in a CORT-mediated loss of CB1R signaling and, consequently, GABA synapses only exhibit LTP(GABA). These observations indicate that CB1R signaling promotes LTD(GABA) and gates LTP(GABA). Furthermore, the satiety state of an animal, through regulation of eCB signaling, determines the polarity of activity-dependent plasticity at GABA synapses in the DMH.

Corticosteroid hormones in the central stress response: quick-and-slow.

Recent evidence shows that corticosteroid hormones exert rapid non-genomic effects on neurons in the hypothalamus and the hippocampal CA1 region. The latter depend on classical mineralocorticoid receptors which are accessible from the outside of the plasma membrane and display a 10-fold lower affinity for corticosterone than the nuclear version involved in neuroprotection. Consequently, this 'membrane' receptor could play an important role while corticosteroid levels are high, i.e. during the initial phase of the stress response. We propose that during this phase corticosterone promotes hippocampal excitability and amplifies the effect of other stress hormones. These permissive non-genomic effects may contribute to fast behavioral effects and encoding of stress-related information. The fast effects are complemented by slower glucocorticoid receptor-mediated effects which facilitate suppression of temporary raised excitability, recovery from the stressful experience and storage of information for future use.

Neuroendocrine hypothesis of aging: the role of corticoadrenal steroids.

The age-related modifications of neuroendocrine secretions normally capable of integrative activity in the whole body might partly promote and amplify many aging phenomena. The quantitative and qualitative changes of hypothalamus-pituitary-adrenal axis are a significant example. The dampening of cortisol and dehydroepiandrosterone (DHEA) circadian fluctuation and the progressive decrease of DHEA/cortisol ratio are at the basis of multiple clinical implications: the shift from anabolic to catabolic status, the activation of atherosclerosis progression, the deterioration of immune competence, the impairment of cognitive and affective performances and the glico- and lipometabolic disorders. The hypothesis of a DHEA supplementation strategy comes out from these premises.

Cat exposure induces both intra- and extracellular Hsp72: the role of adrenal hormones.

Heat-shock proteins (Hsp) play an important role in stress physiology. Exposure to a variety of stressors will induce intracellular Hsp72, and this induction is believed to be beneficial for cell survival. In contrast, Hsp72 released during stress (extracellular Hsp72; eHsp72) activates pro-inflammatory responses. Clearly, physical stressors such as heat, cold, H(2)O(2), intense exercise and tail shock will induce both intra- and extracellular Hsp72. The current study tested whether a psychological stressor, cat exposure, would also trigger this response. In addition, the potential role of adrenal hormones in the Hsp72 response was examined. Adult, male Sprague Dawley rats were either adrenalectomized (ADX) or sham operated. Ten days post-recovery, rats were exposed to either a cat with no physical contact or control procedures (n = 5-6/group) for 2 h. Levels of intracellular Hsp72 were measured in the brain (frontal cortex, hippocampus, hypothalamus, dorsal vagal complex) and pituitary (ELISA). Levels of eHsp72 (ELISA) and corticosterone (RIA) were measured from serum obtained at the end of the 2-h stress period. Rats that were exposed to a cat had elevated intracellular Hsp72 in hypothalamus and dorsal vagal complex, and elevated eHsp72 and corticosterone in serum. Both the intra- and extracellular Hsp72 responses were blocked or attenuated by ADX. This study demonstrates that cat exposure can stimulate the Hsp72 response and that adrenal hormones contribute to this response.

Cortisol abnormality as a cause of elevated estrogen and immune destabilization: insights for human medicine from a veterinary perspective.

For more than 35 years the author has treated multiple serious diseases in cats and dogs by correcting an unrecognized endocrine-immune imbalance originating with a deficiency or defect of cortisol. The cortisol abnormality creates a domino effect on feedback loops involving the hypothalamus-pituitary-adrenal axis. In this scenario, estrogen becomes elevated, thyroid hormone becomes bound, and B and T cells become deregulated. Diseases with this aberration as a primary etiological component range from allergies to severe cases of autoimmunity to cancer. The author has consistently identified excess estrogen or "estrogen dominance" as part of an endocrine-immune derangement present in many common diseases of dogs and cats. Ninety-percent of these cases involve spayed females and neutered or intact males, so the elevated estrogen cannot be attributed to ovarian activity. The author identifies the adrenal cortex as a source of the imbalance, which produces a variety of vital hormones. The author has developed an endocrine-immune blood test that measures cortisol, total estrogen, T3 and T4, and IgA, IgG, and IgM antibody levels. The protocol for corrective therapy involves the use of various cortisone medications, either standard pharmaceutical compounds or a natural bio-identical preparation made from an ultra extract of soy. The author's clinical success and the growing clinical applications of low-dosage cortisone therapy for humans strongly argue for sustained research into the nature, magnitude, and impact of cortisol defects, including an associated estrogen-immune problem, in the etiology of disease.

Participation of corticosteroids and effects of indomethacin on the acute inflammatory response of rats fed n-6 or n-3 polyunsaturated fatty acid-rich diets.

We have previously shown that both n-3 (fish oil) and n-6 (soybean oil) PUFA-rich diets reduce carrageenan-induced paw edema in rats. The present study evaluated the role of corticosteroids, and the effect of indomethacin on this response. Basal (pre-carrageenan) levels of corticosterone were elevated in both lipid diets compared to the chow diet. During inflammation, corticosterone levels increased to a similar extent in the chow and lipid diets. With 2.0 mg/kg indomethacin, edema was reduced in the chow diet and the n-3 diet, while it was not changed in the n-6 diet. In contrast, the 16.6 mg/kg dose of indomethacin induced a mild increase in edema in the chow diet but a pronounced edema increase in the lipid diets. The increase in corticosterone levels induced by carrageenan was either reduced (chow) or completely abolished (lipids) by the treatment with the higher dose of indomethacin, compared to both the control (untreated) group, and the lower dose of indomethacin. These data indicate that both acute inflammation and the response to an antiinflammatory drug were attenuated by n-3 or n-6 PUFA-rich diets. They also showed that indomethacin can have anti- or proinflammatory properties reflecting the extent of the corticosterone inhibition by indomethacin.

The hypothalamic pituitary axis in the fetus and newborn.

Glucocorticoid receptor activation in the fetal lung triggers maturation necessary for extra-uterine life. Antenatal treatment with betamethasone and dexamethasone has lowered severity of respiratory distress in very low birth weight infants, and dexamethasone given postnatally has resulted in short-term improvement in chronic lung disease. Recently, however, surfactant therapy has diminished the differential benefit of antenatal glucocorticoid treatment, and it has been difficult to show that postnatal dexamethasone therapy improves survival. Treated infants may have reduced weight gain, adrenal suppression, increased incidence of intestinal perforation and infection, and long-term developmental and metabolic problems. Recent data suggest that the fetal hypothalamic/pituitary/adrenal axis is active early and is precisely structured for an intricate sequence of specifically fetal developmental events, which may be deranged by dexamethasone therapy. We consider data suggesting that persistence of the fetal pattern in some premature infants constitutes adrenal insufficiency, and that therapy at stress replacement doses with less potent glucocorticoids might avoid side effects seen with traditional regimens.

Corticosteroids and leukotrienes: chronobiology and chronotherapy.

Corticosteroids and leukotrienes play opposite roles in asthma. Corticosteroids, both endogenously secreted and exogenously administered, are antiinflammatory and are very effective in the treatment of asthma. They have also been evaluated chronotherapeutically and have been found to be very effective in reducing the enhanced airway inflammation and decrement in lung function associated with nocturnal worsening of asthma. Leukotrienes are potent proinflammatory and spasmogenic mediators that have been shown to be increased at night in patients with nocturnal asthma (NA). Leukotriene modifiers, a new class of medications to treat asthma, improve, but do not abolish, the symptoms and decrement in lung function associated with nocturnal asthma. However, they have not been evaluated chronotherapeutically. This article addresses the roles of corticosteroids and leukotrienes in nocturnal asthma and their position as therapeutic agents or targets for therapy.

Acupuncture: a review of its history, theories, and indications.

BACKGROUND: The National Institutes of Health recently recommended acupuncture as an effective tool for the treatment of various health problems. Acupuncture is an old technique but has been popular in the United States only since 1972. Its history, theories, and indications are not well known to the medical community. METHODS: We reviewed the literature to gather information on the history, techniques, physiology, indications, adverse effects, and opposing views to acupuncture. RESULTS: The mechanism by which acupuncture works involves neurotransmitters and adrenocorticotropic hormones. It appears to be effective in the treatment of pain, nausea, and drug detoxification and in stroke victims. Studies suggest acupuncture is no more effective than placebo. Acupuncture side effects have rarely been reported. CONCLUSIONS: Acupuncture appears to be a safe and effective alternative medical therapy for certain health problems. More controlled research is necessary to better understand the range of its clinical application.

Adrenal-dependent modulation of the catalytic subunit isoforms of the Na+-K+-ATPase in aorta.

Na+-K+-ATPase gene expression and activity were studied in aortas from adrenalectomized (ADX) rats and ADX rats with deoxycorticosterone supplement (ADX-DOCA). Northern analysis of RNA from ADX rats revealed a significant decrease in alpha2-mRNA levels (38.5 +/- 8.3% of control, P < 0.01) that was prevented by DOCA (P < 0.05). A decrease to 55.8 +/- 7.7% in alpha2-isoform protein was observed 8 days after adrenal removal (P < 0.05); DOCA reversed this effect (90.8 +/- 10.5%). Adrenalectomy induced a decrease of 68.5 +/- 4.5% in beta1-mRNA (P < 0.01) and 52.7 +/- 8.3% in ADX-DOCA rats (P < 0.01). Also, a reduction in beta1-isoform protein that was not prevented by DOCA was detected after adrenalectomy (47.1 +/- 11%, P < 0.01). In contrast, no differences in alpha1-mRNA or -protein levels were observed. Vascular sodium pump activity was reduced to 59.8 +/- 4.6% of control values after adrenalectomy (P < 0.01); this reduction was reversed by DOCA. Our data indicate that corticosteroids regulate Na+-K+-ATPase isoform expression and activity in vascular tissue in vivo, suggesting a mineralocorticoid-dependent modulation of alpha2-Na+-K+-ATPase gene expression in aorta, with beta1-isoform expression dependent on the presence of glucocorticoids.

Systemic and luminal influences on the perinatal development of the gut.

At birth, the mammalian gastrointestinal tract (GIT) must be able to support a shift from mainly parenteral nutrition in the fetus (via the placenta) to enteral nutrition in the neonate. In the perinatal period the GIT therefore undergoes enhanced growth as well as morphological and functional differentiation, and this maturational programme is influenced by a complex interplay of local, systemic and luminal factors. This review shows how systemic and luminal factors may influence GIT development in the perinatal period of the pig and sheep, two long-gestation species. Adrenocortical hormones play a pivotal role in the prepartum maturation of the GIT in addition to their better known effects on the development of many other tissues and body systems. More particularly, in the fetal pig and sheep, the prenatal development of gastric acid and gastrin secretion, and of GIT hydrolase activities (chymosin, pepsin, amylase, lactase, aminopeptidases) is influenced by cortisol. Additionally, glucocorticoids exert effects throughout the GIT by influencing morphological, cytological, and functional differentiation. Since the GIT epithelial cells comprise a renewing cell population there are also changes in cell kinetics. In addition to systemic factors, the presence of growth factors, hormones and nutrients from swallowed amniotic fluid (fetus) and colostrum (neonate) may influence GIT development. In utero, fetal fluid ingestion has been shown to modulate tissue growth, macromolecule and immunoglobulin transport, enterocyte differentiation, cell turnover and activity of brush-border hydrolases. These effects may be mediated via regulatory peptides (e.g. insulin-like growth factor I, gastrin-releasing peptides, insulin, epidermal growth factor, gastrin). A physiological role of luminally derived growth factors is supported by a number of unique structural and functional adaptations of the GIT in the fetus and neonate (low luminal proteolysis, intestinal macromolecule transport). Thus, in the pig and sheep, both systemic and luminal factors appear to play critical roles in GIT development in the perinatal period.

[The antiulcer effect of corticosteroids and the blood flow in the gastric mucosa]. / Protivoiazvennyi éffekt kortikosteroidov i krovotok v slizistoi obolochke zheludka.

Intravital microfilming by means of dark-field contact epiobjective was used for investigation of the role of gastric microcirculation in antiulcerogenic action of corticosteroids in rats. Microvascular volume blood flow velocity was calculated from measurements of red cell velocity and vessel diameters. There was compared gastric submucosal and mucosal microcirculation as well as gastric ulceration after water-immersion stress in rats with normal function of hypothalamo-pituitary-adrenocortical (HPA) axis and in rats with insufficiency of corticosteroid production, induced by blockade of the HPA axis. The 3h stress induced gastric ulcerations, dilatation of mucosal microvessels and a significant decrease of volume blood flow in submucosal microvessels. These changes were greater in rats with blockade of HPA axis than in animals with normal corticosteroid production. Replacement corticosterone therapy decreased the effects of HPA axis blockade. Thus corticosteroids which are produced during stress restricted the reduction of volume blood flow in submucosal microvessels, the dilatation of mucosal microvessels as well as gastric ulcerations. These findings indicate that corticosteroids exert their antiulcerogenic action via the mechanism of improvement of gastric microcirculation.

Removal of adrenal steroids from the medium reverses the stimulating effect of catecholamines on corticotropin-releasing hormone neurons in organotypic cultures.

An organotypic culture system of anterior hypothalamic slices was developed for studying the secretory responses of corticotropin-releasing hormone (CRH) neurons to corticosteroid-catecholamine interactions. The standard culture medium included 5% horse serum containing 50 micrograms/l cortisol. In 1- to 3-day cultures, the tissue viability was demonstrated by the presence of arginine vasopressin immunolabeled perikarya and axons in the paraventricular nucleus and by sustained tissue concentrations of CRH (around 50 pg/mg protein). However, immunoreactive CRH neurons were not detectable in cultures in the standard medium. Exposure of cultures to high K+ (56 mM) in the medium induced a ten-fold increase in basal CRH release which was completely abolished in a Ca(2+)-free medium containing 2 mM EGTA. Noradrenaline (NA) triggered CRH release in a dose-dependent (1-20 microM) and time-dependent (0.5-6 h) manner. Removal of corticosteroids from the media by charcoal treatment led to (1) the visualization of immunolabelled CRH perikarya and fibers and a 55% rise in CRH content of the paraventricular nucleus tissue and (2) to a five-fold increase in CRH release. Both effects were reversed by supplementation of the culture medium with corticosterone (50 micrograms/l). Under steroid-free conditions, NA (1-10 microM) not only failed to induce CRH release, but strongly inhibited the consistent baseline in CRH release. This was reminiscent of a similar corticosteroid-dependent inversion of the NA effect on the hypothalamic-pituitary-adrenal axis described in vivo. Overall, these results are direct evidence of complex corticosteroid-catecholamine interrelationships as major regulatory factors of the hypothalamic-pituitary-adrenal axis.

Adrenal steroid receptors: interactions with brain neuropeptide systems in relation to nutrient intake and metabolism.

The glucocorticoid, corticosterone (CORT), is believed to have an important function in modulating nutrient ingestion and metabolism. Recent evidence described in this review suggests that the effects of this adrenal hormone are mediated through two steroid receptor subtypes, the type I mineralocorticoid receptor and the type II glucocorticoid receptor. These receptors, which have different affinities for CORT, respond to different levels of circulating hormone. They mediate distinct effects of the steroid, which can be distinguished by the specific nutrient ingested and by the particular period of the circadian cycle. Under normal physiological conditions, the type I receptor is tonically activated, either by low basal levels of circulating CORT (0.5-2 microgram %) normally available across the circadian cycle or possibly by the mineralocorticoid aldosterone. This type I activation is required for the maintenance of fat ingestion and fat deposition that occurs during most meals of the feeding cycle. In contrast, the type II receptor is phasically activated by moderate levels of CORT (2-10 micrograms %) normally reached during the circadian peak. Activation of this receptor is required for the natural surge in carbohydrate ingestion and metabolism that is essential at the onset of the active feeding cycle when the body's glycogen stores are at their nadir, and gluconeogenesis is needed to maintain blood glucose levels. This receptor is also activated during periods of increased energy requirements, such as, after exercise and food restriction, when CORT levels rise further (> 10 micrograms %) and when its catabolic effects on fat and protein stores predominate to provide additional substrates for glucose homeostasis. These functions of CORT on fat and carbohydrate balance are mediated, in part, by type I and type II receptors located within the hypothalamic paraventricular nucleus, which is known to have key functions in controlling nutrient intake and metabolism, as well as circulating CORT levels. Moreover, the type II receptors within this nucleus, in addition to the arcuate nucleus, may interact positively with the peptide, neuropeptide Y, and the catecholamine, norepinephrine, both of which act to enhance natural carbohydrate feeding and CORT release at the onset of the natural feeding cycle. Thus, under normal conditions, endogenous CORT has a primary function in controlling nutrient ingestion and metabolism over the natural circadian cycle, through the coordinated action of the type I and type II steroid receptor systems. Through this action, CORT has impact on total caloric intake and body weight gain over the long term.(ABSTRACT TRUNCATED AT 400 WORDS)

Oxytocin binding sites in rat limbic and hypothalamic structures: site-specific modulation by adrenal and gonadal steroids.

Basal density and estrogen induction of oxytocin binding sites in limbic and hypothalamic structures of the rat brain were investigated by semi-quantitative autoradiography following chronic administration of dexamethasone or progesterone. The selective oxytocin receptor antagonist d(CH2)5[Tyr(Me)2,Thr4,Tyr-NH2(9)] ornithine-vasotocin was used as a ligand for oxytocin binding sites. Estrogen administration increased ligand binding in all sites investigated. Dexamethasone treatment significantly increased ligand binding in the bed nucleus of the stria terminalis, lateral ventral septum and amygdala to an extent which was comparable to that of estradiol alone. In the hypothalamic ventromedial nucleus, dexamethasone significantly decreased basal levels of oxytocin binding. Estrogen administration subsequent to dexamethasone failed to cause a further increase in oxytocin binding in all structures investigated. Chronic progesterone treatment significantly increased basal oxytocin receptor density in the limbic structures, decreased it in the ventromedial nucleus, and prevented estrogen-induced increases in ligand binding in all areas studied with the exception of the medial preoptic area. These findings demonstrate that, in addition to gonadal steroids, glucocorticoids differentially and site-specifically modulate cerebral oxytocin binding sites. The evidence for glucocorticoid and gestagen influences on oxytocin receptors and their inducibility by estrogen may be relevant to the understanding of mechanisms leading to impairment of oxytocin-related behaviours.

Role of tissue renin in the pathophysiology of hypertension in TGR(mREN2)27 rats.

A transgenic rat line, TGR(mREN2)27, was established by introducing the murine Ren-2 gene into the genome of rats by microinjection techniques. These rats exhibit severe hypertension, making them an interesting model in which to study the role of renin in the pathophysiology of hypertension. However, although the additional renin gene is the only genetic difference compared with control rats, the exact mechanism of hypertension in TGR(mREN2)27 rats is still unclear. It cannot be attributed to a stimulation of the endocrine renin-angiotensin system or to an overexpression of renin in the kidney, since plasma and kidney renin and renin gene expression in the kidney are low in these animals. Here we describe recent progress made toward elucidating mechanisms of hypertension in TGR(mREN2)27 rats. 1) TGR(mREN2)27 rats were bred to homozygosity. The development of high blood pressure in homozygous rats is accelerated compared with that of heterozygous rats. This is paralleled by a higher mortality rate in homozygous TGR(mREN2)27 rats. Blood pressure and mortality rate of homozygous transgenic rats were effectively reduced by 10 mg captopril per kilogram body weight. 2) Treatment of 8-week-old heterozygous TGR(mREN2)27 rats with 10 mg/kg body wt per day of the angiotensin II receptor antagonist DuP 753 for 4.5 weeks normalized blood pressure. After withdrawal of the drug, blood pressure increased rapidly, reaching control levels after 3 weeks. In another group of TGR(mREN2)27 rats treated with 0.5 mg/kg per day, there was no change in blood pressure. Plasma renin and plasma angiotensin II were significantly higher in the high-dose group compared with the low-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)