摘要:

During the postnatal period from day 2 to day 10 of life, basal and stress-induced adrenocorticotropic hormone (ACTH) and corticosterone releases are low as compared with adults. This period has been called the ‘stress-hyporesponsive period’, and its mechanisms are yet undetermined. In this study, we have tested the effects of substances excitatory to neuronal activity on the hypothalamic-pituitary-adrenal (HPA) axis. In 7-day-old rats, administration of the excitatory amino acid (EAA) agonists N-methyl-D-aspartic acid (NMA), quisqualic acid, and kainic acid (KA) induced a large increase in plasma ACTH and corticosterone concentrations. All three EAA induced a rapid and potent stimulation of ACTH release within 30 min, the effect on corticosterone secretion being weaker. KA was the more potent EAA, followed by NMA and quisqualic acid. The effect of NMA on the HPA axis was inhibited by pretreatment with a competitive antagonist to N-methyl-D-aspar-tic acid receptors, D, L-2-amino-5-phosphonovaleric acid. We next sought to determine which level of the HPA axis was affected by EAA administration. Several EAA (glutamic acid, N-methyl-D-aspartic acid, and KA from 10-5 to 10-2M) had no stimulating action on ACTH release from 7-day-old anterior pituitary glands incubated in vitro. In vivo, the stimulating effect of NMA and KA on in vivo ACTH release was blocked after passive immunization with an anti-corticotropin-releasing hormone antiserum, but not after injection of an anti-arginine vasopressin antiserum. These results suggest that during stress-hyporesponsive period, the HPA axis can be stimulated by excitatory substances acting at the hypothalamic or suprahypothalamic le

ISSN:0028-3835    

DOI:10.1159/000126344

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

To further explore the differential effects of peripherally and centrally derived hypercortisolism on neurohormonal systems implicated in the pathophysiology of mood and cognitive disturbances, we examined the cerebrospinal fluid (CSF) concentrations of immunoreactive somatostatin (IR-SRIF) in patients with Cushing’s disease and major depression and the relationship of these levels to CSF immunoreactive corticotropin-releasing hormone (CRH) concentrations and urinary free cortisol excretion. In particular, since CSF SRIF levels consistently have been shown to be reduced in depression, we wished to assess whether decreased centrally directed SRIF was more likely a primary or a secondary factor in the hypercortisolism of major depression. CSF SRIF levels were significantly reduced in 11 patients with documented Cushing’s disease and in 1 patient with ectopic adrenocorticotropic hormone secretion as compared with both 41 healthy volunteers (19.4 ± 2.9 vs. 37.4 ± 1.5 pmol/l; p < 0.01) and 28 patients with major depression (30.2 ± 2.4 pmol/l; p < 0.05), whose CSF SRIF levels were also significantly reduced as compared with controls (p < 0.05). CSF SRIF levels in the Cushing’s disease patients correlated positively with CSF CRH (r = 0.64; p < 0.025), suggesting that either the sustained hypercortisolism in these patients and/or its suppression of central CRH secretion contributed to the reduction in SRIF. A more modest but significant correlation between CSF SRIF and CSF CRH was observed in the healthy volunteers (r = 0.37; d.f. = 37; p < 0.02); in the depressed patients, no linear relationship, but rather an inverted U-shaped relationship was found which significantly fit by a quadratic function (r2 = 0.90; d.f. = 22; p < 0.001). In the depressed patients, the CSF SRIF levels also showed an inverted quadratic relationship with urinary free cortisol excretion (r2 = 0.87; d.f. = 16; p < 0.001). These findings, together with those from recent preclinical and human volunteer studies, suggest that CRH is a positive modulator of central SRIF release under physiological conditions, while glucocorticoid excess tends to suppress SRIF. These data are of interest in the light of evidence suggesting an involvement of SRIF in functions such as mood regulation, learning, and memory which are disturbed in both Cushing’s disease and major

ISSN:0028-3835    

DOI:10.1159/000126345

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Apoptosis was investigated by electron and light microscopy in the anterior pituitary gland of the male Fischer rat in which hyperplasia of prolactin-secreting cells had been induced by estrogen implanted subcutaneously for 6 weeks. Counts by light microscopy of apoptotic cells and cells containing phagocytosed apoptotic bodies increased during a period of 44 h after estrogen withdrawal. Necrosis was present but was not prominent. Administration of bromocriptine after estrogen withdrawal increased apoptotic counts to nearly double those in the absence of bromocriptine. Bromocriptine caused some increase in necrosis. Apoptosis occurred in prolactin-secreting cells identified by immunostaining and in other cells. Phagocytosed apoptotic bodies were seen in folliculo-stellate and not in other cells. It is concluded that apoptosis occurs in the anterior pituitary gland and is induced by bromocriptine. Phagocytosis of apoptotic bodies is a function of the folliculo-stellate cells.

ISSN:0028-3835    

DOI:10.1159/000126346

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Levels of hypothalamic corticotropin-releasing hormone (CRH) mRNA and plasma glucocorticoids vary diurnally as a result of circadian influences on the hypothalamopituitary-adrenal axis. CRH mRNA expression increases from morning to afternoon in rats but decreases rapidly near the onset of dark as glucocorticoids reach peak concentrations in plasma. Since glucocorticoids are normally inhibitory on hypothalamic CRN mRNA expression, we determined whether the glucocorticoid secretion at the diurnal peak reduced CRH mRNA concentration in the evening. We found that adrenalectomy did not prevent the decrease in CRH mRNA levels near the onset of dark. It appears that the drop in CRH mRNA expression occurs via a steroid-independent mechanism. While the mean CRH mRNA level increased after adrenalectomy, the shape of the CRH mRNA rhythm remained unchanged except in the morning. Interestingly, adrenalectomy increased CRH mRNA levels disproportionately in the morning, producing a sharp rise followed by a plateau during the light phase instead of the gradual rise observed in intact animals. We subsequently treated adrenalectomized animals with corticosterone pellets to determine whether a constant steroid signal was sufficient in restoring the normal shape of the mRNA rhythm dring the lihgt phase. Results indicate that the endogenous steroid rhythm is not necessary for generating the normal CRH mRNA rhythm during the light phase. Instead, a constant exposure to corticosterone at approximately 50% of the daily mean (2.4-3 µg/dl) appears to be sufficient for regulation of the mRNA rhythm. Additionally, corticosterone replacement achieving a lower concentration of 1.5 µg/dl seems effective in regulating basal ACTH secretion in the morning despite being insufficient for regulating CRH or POMC mRNA levels at this time. We conclude that the shape of the diurnal CRH mRNA rhythm in the hypothalamus is largely independent of steroid regulation, although a steroid-dependent component appears to exist during the circadian nadir. A constant steroid level in the range primarily for type I corticosteroid receptor binding can reinstate CRH mRNA variation which occurs during the light phase, indiating that corticosterone oscillation is not necessary for diurnal CRH mRNA regulation. Finally, corticosterone may regulate basal ACTH secretion more effectively than CRH mRNA expression at the diurnal nadi

ISSN:0028-3835    

DOI:10.1159/000126347

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

The effect of chronic ethanol exposure on proopiomelanocortin (POMC) mRNA accumulation, β-endorphin (β-EP) levels as well as incorporation of [3H]-phenylalanine into β-EP-related peptides was investigated in the rat hypothalamus. Animals were treated with an ethanol-containing liquid diet for 15 days. Both sucrose pair-fed and ad libitum-fed control groups were included. The levels of immunoreactive β-EP, as well as the relative proportions of nonacetyl and acetyl forms of β-EP in the hypothalami of the ethanol-treated rats were not significantly different from those in the sucrose and lab chow fed control rats. Northern blot analysis of total hypothalamic RNA indicated that ethanol-treated rats had higher POMC mRNA levels than sucrose pair-fed and control rats. Quantitation of the in vitro incorporation of [3H]-phenylalanine into POMC, β-lipotropin and β-EP by the hypothalamus, using immunoprecipitation and polyacrylamide disc-gel electrophoresis with sodium dodecyl sulfate, revealed that the increased hypothalamic POMC mRNA content was associated with increased incorporation of [3H]-phenyl-alanine into POMC by the hypothalami of the ethanol-treated rats. It is concluded that chronic ethanol can alter the expression of the POMC gene in the hypoth

ISSN:0028-3835    

DOI:10.1159/000126348

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

In the ovariectomized rhesus monkey, estradiol (E2) markedly reduces the frequency of the GnRH pulse generator as monitored by LH pulse frequency and the concurrent changes in hypothalamic electrical activity, an action mimicked by morphine. In addition, the duration of the increments in multiunit electrical activity (MUA volleys) that precede each LH pulse is decreased by estrogen administration, an action also shared by morphine. The role of endogenous opioids in these actions of E2 was investigated in 8 ovariectomized animals restrained in primate chairs. They were fitted with indwelling cardiac catheters and with bilateral arrays of recording electrodes chronically implanted in the mediobasal hypothalamus. Physiological serum E2 levels achieved by subcutaneous implantation of E2-containing Silastic capsules increased MUA volley interval from 50.8 ± (SEM) 1.6 min in the control period to 81.1 ± 6.2 min following E2. Mean MUA volley duration decreased from 21.9 ± 1.0 to 13.0 ± 0.7 min. The placement of empty Silastic capsules had no effect on MUA volley duration or interval. Naloxone administration (2.5 mg bolus followed by a 1 mg/h infusion lasting 4-8 h) completely (n = 4) or partially (n = 2) blocked the effects of E2 on MUA volley interval in 6 of the 8 monkeys, and was without effect in the remainder. In contrast, however, naloxone had little or no effect on the action of E2 on MUA volley duration, (13.0 ± 0.7 vs. 14.0 ± 0.9 min). These findings suggest that the inhibitory action of E2 on GnRH pulse generator frequency, like that of all other gonadal steroids studied to date, may be mediated by endogenous opioids. The equally striking inhibitory effect of E2 on pulse generator MUA volley duration, however, an effect that can also be replicated by morphine administration, seems to be principally effected by other mecha

ISSN:0028-3835    

DOI:10.1159/000126349

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

Using quantitative autoradiography, the density of melatonin binding sites has been measured in the rat pars tuberalis (FT) and suprachiasmatic nuclei (SCN) every 4 h throughout a 24-hour period in animals kept in a light regime of 12L/12D (with lights on at 07.00 h). Slices of PT and SCN were incubated in the presence of 180 and 172 pM, respectively, of 2-l25I-melatonin. In both structures investigated, specific 2-125I-melatonin binding sites showed similar rhythms throughout the 24-hour period with a maximum at 16.00 h (PT: 46.9 ± 2.8 fmol/mg protein, n = 5 and SCN: 5.12 ± 0.30 fmol/mg protein, n = 5) and a minimum at 4.00 h (PT: 28.5 ± 4.5 fmol/mg protein, n = 5 and SCN: 3.07 ± 0.39 fmol/mg protein, n = 5). Similar experiments performed on PT of animals kept in constant light (LL) for 3 days revealed a lack of variations of melatonin binding site density, all the values being significantly higher than those of the respective 12L/12D group (concentration of 2-125I-melatonin used: 180 pM). All these preliminary results were confirmed by saturation studies performed at 16.00 and 4.00 h using quantitative autoradiography and in 12L/12D animals, using radioreceptor binding assays on isolated PT membranes. In 12L/12D animals, the maximum number of melatonin binding sites (Bmax) of both SCN and PT was significantly higher at 16.00 h than at 4.00 h. In all these cases, however, the dissociation constant (Kd) failed to show any significant daily variation. Plasma melatonin concentrations measured by radioimmunoassay at the same time points showed a clear rhythm with a nocturnal peak present in 12L/12D animals (24.00 and 4.00 h) and a lack of variation in LL-exposed animals. These findings (1) show that there is no tissue-specific regulation of melatonin receptors between PT and SCN and (2) suggest that the daily variations in plasma melatonin concentrations could be implicated in the regulation of the density of melatonin binding sites both in the rat PT and SCN, probably by a mechanism of desensitization of the melatonin binding sites by melatonin its

ISSN:0028-3835    

DOI:10.1159/000126350

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

It was found in our earlier experiments that infusion of β-endorphin (β-End) into the 3rd brain ventricle in sheep elicited a differential effect on the secretion of cortisol under physiological and stress conditions. Under physiological conditions it elevated the level of cortisol in the peripheral blood, while in stressed animals it suppressed it. To obtain further support for the suppressive action of β-End on cortisol secretion under stress conditions a β-End antiserum was infused into the 3rd ventricle of the brain in stressed and nonstressed sheep and the concentration of plasma cortisol was measured. Stress was induced by mild electric foot shock. Infusion of the β-End antiserum during stimulation enhanced the plasma cortisol values, when compared with those obtained during the infusion of rabbit hyperimmune serum containing anti-guinea pig γ-globulins or saline. Moreover, during the infusion of β-End antiserum some aggravation of stress symptoms expressed by the increase of restlessness and higher frequency of defecations and urinations was observed. Additional experiments carried out to study the effect of β-End on prolactin (PRL) secretion showed that this opioid induced a very high secretion of PRL in stressed animals. On the basis of these data and the known suppressive action of PRL on the corticosterone response to stress in the rat, we suggest that the suppressive action of β-End on cortisol secretion in stressed sheep could be caused by the action of PRL. Conversely, blockade of β-End function by the infusion of β-End antiserum and suppression of PRL secretion could enhance secretion of cortisol and aggravate stress symptoms in stimul

ISSN:0028-3835    

DOI:10.1159/000126351

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

It is well known that GHRH-induced GH secretion decreases after orchidectomy. To verify if testicular factors other than testosterone are involved in this effect, the GHRH-induced GH secretion and testosterone plasma levels were compared in adult male rats that were either intact, treated with ethylene dimethane sulphonate (EDS) (a specific toxin for Leydig cells), orchidectomized or testosterone-treated orchidectomized. We found that testosterone plasma levels and ventral prostate weight decreased to a similar extent in orchidectomized and EDS-treated males. GHRH-induced GH secretion only decreased in orchidectomized males. We conclude that testicular factors, other than androgens, increase GHRH-induced GH secretion.

ISSN:0028-3835    

DOI:10.1159/000126352

出版商:S. Karger AG    

年代:1993

数据来源: Karger

摘要:

It has been suggested that hypothalamic median eminence (ME) might be a control site for luteinizing hormone-releasing hormone (LHRH) release. Thus, stimulatory and/or inhibitory inputs acting at this site might be involved in regulating LHRH release from the ME and, therefore, luteinizing hormone (LH) release from the anterior pituitary. Since a role for neuropeptide Y (NPY) on LH release has been suggested, we hav hypothesized that NPY might act in the ME to control preovulatory LHRH release in hens. To examine this possibility we have detrmined: (a) the immunocytochemical distribution of LHRH and NPY in the ME of the hen, (b) the basal and NPY-stimulated release of LHRH in vitro from the ME of hens undergoing a natural or a premature preovulatory surge of LH, and (c) the tissue content of LHRH and NPY in microdissected MEs, at various times before and during a natural or a premature preovulatory surge of LH. A potential role for NPY on LHRH release in the ME is suggested for the following reasons, (a) There are opportunities for synaptic interactions between NPY and LHRH-containing axons at this site. LHRH-containing cell bodies localized in the anterior hypothalamus/medial preoptic area project to the ME. NPY-containing perikarya, concentrated in the ventromedial aspect of the arcuate nucleus, might contact LHRH processes going to the ME and/or might themselves send axons to the ME, (b) Addition of NPY to the incubation media increases LHRH release from microdissected ME tissue of hens killed at the time of the natural preovulatory surge of LH, but not in hens killed 7 h before the occurrence of this surge. However, the stimulatory effect of NPY on LHRH release can be induced at this latter time when a premature LH surge is elicited. While the natural preovulatory surge of LH occurs 4 h before the second ovulation in a sequence (C2 ovulation), administration of progesterone (P4) 10-14 h before the expected natural C2 ovulation advances the natural LH surge by 7-8 h. Thus, NPY might act as a physiological stimulus of LHRH release at the ME during the preovulatory surge of LH. This is suggested since in vitro basal LHRH release from denervated ME tissue does not change before and during the natural or the premature LH surge. Therefore, preovulatory release of LHRH in vivo might be under a continuous drive from stimulatory inputs to the LHRH neuron and NPY might be one of these stimulating factors, (c) An acute preovulatory decrease in ME-NPY tissue content is consistent with its putative role on preovulatory LHRH release. During both the natural and the premature preovulatory period, NPY content reaches nadir values at the time of the LH surge, which occurs 7-8 h earlier in the premature than in the natural model. In conclusion, NPY might be acting at the median eminence as a physiological stimulus for preovulatory LHRH release.

ISSN:0028-3835    

DOI:10.1159/000126353

出版商:S. Karger AG    

年代:1993

数据来源: Karger