Keiko Arai

Corticotropin-releasing factor receptor type 1 mediates emotional stress-induced inhibition of food intake and behavioral changes in rats

We investigated whether corticotropin-releasing factor (CRF) receptor type 1 (CRFR1) is involved in emotional stress-induced inhibition of food intake and behavioral changes in rats. The inhibition of food intake and increase in locomotor activity induced by emotional stress using a communication box were reversed by both intracerebroventricular injection of alpha-helical CRF (9-41), a non-selective CRF receptor antagonist, and intraperitoneal injection of a selective non-peptidic CRFR1 antagonist. These results suggest that CRFR1 mediates at least in part the emotional stress-induced inhibition of feeding behavior and increase in locomotor activity.

Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas

OBJECTIVE The level of growth hormone (GH), growth hormone secretogogue (GHS) and GHS receptor (GHSR) messenger ribonucleic acid (mRNA) expression has been reported as being higher in GH‐producing pituitary adenomas than in other types of pituitary adenomas. Recently, ghrelin, an endogenous ligand specific for GHSR, was isolated. Therefore, we attempted to clarify whether ghrelin mRNA is expressed in various types of human pituitary adenoma by competitive reverse transcription‐polymerase chain reaction (RT‐PCR). We also examined the relationship between the levels of ghrelin or GHSR mRNA and hormonal and tumour characteristics in patients with pituitary adenomas.

Both corticotropin-releasing factor receptor type 1 and type 2 are involved in stress-induced inhibition of food intake in rats

RationaleStress-induced inhibition of food intake is reportedly blocked by a selective corticotropin-releasing factor (CRF) type 1 receptor (CRF1) antagonist, suggesting the involvement of CRF1 in the inhibitory mechanism. CRF1 and CRF2 are considered to function in the inhibition of food intake by CRF-related peptides with different time courses.ObjectivesThis study was designed to clarify whether CRF2 is also involved in stress-induced inhibition of food intake and to examine the relation of CRF1 to CRF2 in the inhibitory mechanism.MethodsAntisauvagine-30 (AS-30), a selective CRF2 antagonist, and/or CRA1000, a selective CRF1 antagonist, were pre-administered intracerebroventricularly and intraperitoneally, respectively, to male Wistar rats deprived of food for 24xa0h before the animals were exposed to a 1-h period of stressors and food intake in 1xa0h after stress exposure was examined. The effect of both antagonists on locomotor activity was also examined.ResultsPre-administration of 5–30xa0μg of AS-30 attenuated inhibition of food intake induced by restraint, electric footshock or emotional stress using a communication box. CRA1000 also attenuated the restraint-induced inhibition of food intake at doses of 5 and 10xa0mg/kg body weight. The reversal of restraint-induced inhibition of food intake by co-administration of AS-30 and CRA1000 was not larger than that by AS-30 or CRA1000 alone. Both antagonists did not affect locomotor activity.ConclusionsThese results suggest that not only CRF1, but also CRF2, are involved in stress-induced inhibition of food intake, and that both subtypes of CRF receptor function probably in series in 1xa0h after stress exposure.

Functional polymorphisms in the mineralocorticoid receptor and amirolide-sensitive sodium channel genes in a patient with sporadic pseudohypoaldosteronism

Abstract. Pseudohypoaldosteronism (PHA) is characterized by urinary salt-wasting in infancy resulting from a congenital resistance to aldosterone involving the genes for the mineralocorticoid receptor (MR) and the amiloride-sensitive sodium channel (ENaC). We identified, in a Japanese patient with sporadic PHA, three homozygous substitutions in the MR gene: G215→C215, A754→G754 (Ile180→Val180), C938→T938 (Ala241→Val241), which had previously been reported to occur in healthy populations. Luciferase activities induced by MR with either G215→C215, Ile180→Val180, or Ala241→Val241 substitution were significantly lower than those for wild-type MR with aldosterone at concentrations ranging from 10–11 to 10–9xa0M, 10–8xa0M, or 10–11 to 10–6 M, respectively. A homozygous A→G substitution of the donor splice site of αENaC intronxa04 was found in the patient. The corresponding cDNA exhibited a normal structure, suggesting that this substitution does not alter the splice. The results suggest that each of three MR polymorphisms identified in our patient is functionally and structurally heterogeneous. We hypothesize that two or more functional polymorphisms, any of which exhibits only slight effects on MR or ENaC function and is alone incapable causing PHA, may in the right allelic combination induce the negative salt-conservation characteristic of PHA.

Corticotropin‐releasing factor receptor type 1 is involved in the stress‐induced exacerbation of chronic contact dermatitis in rats

Abstract: Cutaneous diseases such as psoriasis and atopic dermatitis are worsened by psychic stress. We attempted to clarify the involvement of the corticotropin‐releasing factor (CRF) receptor (CRFR) in stress‐induced exacerbation of chronic contact dermatitis in rats. Male Wistar rats, in which chronic contact dermatitis had been induced by 2,4,6‐trinitro‐1‐chlorobenzene (TNCB), were exposed to a 1‐h period of electric foot‐shock following intraperitoneal administration of CRA1000, a selective CRFR type 1 (CRFR1) antagonist, or vehicle everyday for 9u2003days. Histological examination of the skin showed that the epidermis significantly thickened and the number of mast cells in the dermis significantly increased by repeated exposure to stress, and that these changes were blocked by CRA1000. These results suggest that CRFR1 is involved in the stress‐induced exacerbation of chronic contact dermatitis.

Effect of chronic administration of a CRF1 receptor antagonist, CRA1000, on locomotor activity and endocrine responses to stress

Corticotropin-releasing factor (CRF) is involved in the regulation of stress responses. The actions of CRF in the brain are mediated through two distinct CRF receptor subtypes, CRF(1) and CRF(2) receptors. In the present study, we examined the effects in rat of chronic administration of a nonpeptidic CRF(1) receptor-selective antagonist, CRA1000, 2-[N-(2-methylthio-4-isopropylphenyl)-N-ethylamino]-4-[4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl]-6-methylpyrimidine), on locomotor activity, feeding behavior and the hypothalamic-pituitary-adrenal axis. Chronic CRA1000 treatment significantly decreased locomotor activity in the dark phase of the diurnal cycle. However, chronic CRA1000 treatment showed no effect on food and water intake, or on body weight. After a 10-day period of CRA1000 treatment, plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in basal conditions and under immobilization stress were no different from those in rats treated with vehicle. However, CRA1000 administered 2 h before immobilization stress significantly reduced ACTH and corticosterone responses to stress with no effect on basal ACTH and corticosterone concentrations. These results suggest that CRF(1) receptors are involved in the regulation of locomotor activity during the dark period, but are not involved in the regulation of feeding behavior under non-stressful conditions. Furthermore, the results suggest that a 10-day treatment with CRA1000 does not affect hypothalamic-pituitary-adrenal axis activity either under basal conditions or after acute stress.

Non-peptidic corticotropin-releasing hormone receptor type 1 antagonist reverses restraint stress-induced shortening of sodium pentobarbital-induced sleeping time of rats: evidence that an increase in arousal induced by stress is mediated through CRH receptor type 1

Stress shortens sodium pentobarbital (PbNa)-induced sleeping time through corticotropin-releasing hormone (CRH) in rats. We investigated whether this effect of brain CRH is mediated by CRH receptor type 1 (CRHR1) using a non-peptidic CRHR1 antagonist in rats. A 60 min period of restraint significantly shortened PbNa-induced sleeping time. This shortening was completely reversed by peripheral administration of CRHR1 antagonist. These results suggest that the stress-induced increase in arousal is mediated by CRHR1.

The expression of thyrotrophin-releasing hormone receptor 1 messenger ribonucleic acid in human pituitary adenomas.

Thyrotrophin‐releasing hormone (TRH) paradoxically induces the release of growth hormone (GH) when injected intravenously into acromegalic patients, although the mechanism of this action is unknown at present. Several research groups have reported that the level of TRH receptor‐1 (TRHR‐1) mRNA expression is variable in pituitary adenomas, and does not correlate with the degree of paradoxical GH response to TRH administration in a limited number of acromegalic patients. We aimed to compare the expression levels of TRHR‐1 mRNA among various types of pituitary adenoma and to clarify whether these levels correlate with the degree of pituitary hormone response to TRH.

Nicotine suppresses energy storage through activation of sympathetic outflow to brown adipose tissue via corticotropin-releasing factor type 1 receptor

Nicotine is known to stimulate energy expenditure, although the precise mechanism is unclear. To clarify the involvement of corticotropin-releasing factor (CRF) in the mechanism by which nicotine increases energy expenditure, the effect of intraperitoneal injection of nicotine (0.1 or 0.5mg/kg) on the release of noradrenaline (NA), a stimulator of thermogenesis, in brown adipose tissue (BAT) important for energy expenditure was examined in rats. We also examined the effects of CRF receptor subtype antagonists on the nicotine-induced change in BAT NA release. Nicotine significantly increased BAT NA release at a dose of 0.5mg/kg, and the increase was completely blocked by antalarmin, a CRF type 1 receptor antagonist, but not by antisauvagine-30, a CRF type 2 receptor antagonist. These results suggest that nicotine increases energy expenditure by activating BAT function, and that CRF type 1 receptors are involved in the mechanism by which nicotine affects energy balance.

Ghrelin mRNA and GH secretagogue receptor mRNA in human GH‐producing pituitary adenomas is affected by mutations in the α subunit of G protein

objectiveu2002 Ghrelin and its receptor, growth hormone secretagogue (GHS) receptor (GHSR), are expressed in the normal pituitary gland and various types of pituitary adenoma. Somatic mutations in the subunit of Gs α protein (gsp), which led to a constitutive activation of adenylyl cyclase, are reported in GH‐producing pituitary adenomas. We analysed the relationship between ghrelin mRNA and GHSR mRNA expression levels in gsp mutation‐positive and ‐negative GH‐producing pituitary adenomas.