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A. Levy and S. L. Lightman

ABSTRACT

The temporal effect of orally administered bromocriptine on pro-opiomelanocortin (POMC) and prolactin gene expression in male Sprague–Dawley rats was examined using in-situ hybridization histochemistry. Messenger RNA in the anterior and intermediate lobes could be clearly delineated in each section. Administration of bromocriptine resulted in a reduction in hybridization of 35S-labelled cDNA probe to prolactin mRNA from 0·69 × 1012 to 0·29 × 1012 copies bound/g after 150 h. POMC mRNA in the anterior lobe remained unchanged with 0·08 × 1012 copies of probe bound/g for the duration of the experiment, while in the intermediate lobe it decreased from 2·44 × 1012 to 0·44 × 1012 copies of probe bound/g at 150 h. The rate of reduction in intermediate lobe POMC mRNA was similar to that of prolactin mRNA for the first 24 h but was subsequently more rapid and more profound, falling to 20% of the control value at 84 h and to 18% at 150 h.

J. Endocr. (1988) 118, 205–210

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M. S. Harbuz and S. L. Lightman

Successful existence depends on the ability to cope with an immense variety of complex challenges or stressors and to mount an 'appropriate' response to any particular situation. While the concept of stress is readily understood, a definition acceptable to more than a handful of individuals remains elusive. It is necessary therefore at the outset to clarify the context within which we have written the current review. We will utilize a simple definition based on the neuroendocrine response to stressors and for this purpose we shall limit our discussion to those events resulting in the activation of the hypothalamo-pituitary-adrenal (HPA) axis. The final stage of this activation is the secretion of glucocorticoids from the adrenal cortex.

Glucocorticoids have a wide range of actions affecting many aspects of bodily function including metabolism, inflammation and immunity. Glucocorticoids also control their own synthesis and release by completing a negative feedback loop at the level

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M. S. Harbuz and S. L. Lightman

ABSTRACT

In-situ hybridization histochemistry was used to measure corticotrophin-releasing factor mRNA and proenkephalin A mRNA in the paraventricular nucleus (PVN), and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary of the rat. Levels of message were determined at 1, 2, 4 and 8 h after exposure to a variety of physical and psychological stresses. Corticotrophin-releasing factor mRNA in the PVN and POMC mRNA in the anterior pituitary increased in response to i.p. hypertonic saline, restraint and swim stress but not to cold stress. Proenkephalin A mRNA was raised only in response to the physical stress of i.p. injection of hypertonic saline. These results suggest that different afferent pathways and hypothalamic neurotransmitters may be involved in mediating the hypothalamic response to different physical and psychological stresses.

Journal of Endocrinology (1989) 122, 705–711

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K Kondo, A Levy, and S L Lightman

We have used in situ hybridization histochemistry to investigate the effects of maternal thyroidectomy and chronic maternal iodine deficiency on basal neuroendocrine function in rat pups. Specifically, we have measured hypothalamic thyrotrophin-releasing hormone (TRH) and pituitary thyroid-stimulating hormone (TSH) expression together with circulating levels of tri-iodothyronine (T3) in rat pups delivered from and suckled by thyroidectomized or iodine-deficient dams. Because of the close interaction between the thyroid, adrenal and growth hormone axes, we have also examined hypothalamic corticotrophin-releasing hormone (CRH) and growth hormone-releasing hormone (GRH) transcripts at the same time points: birth, 1 month and 2 months of age.

Three weeks after surgical thyroidectomy, adult female Sprague–Dawley rats proved unable to carry pups to term and lactate successfully. Pups delivered from thyroidectomized dams given a small replacement dose of T3 during pregnancy were significantly lighter than controls (84 ± 3%) and had markedly depressed plasma T3 levels (36 ±6% of control). Hypothalamic CRH and GRH transcript levels were significantly decreased in pups at birth (to 8±2·5% and 24 ± 8% of control respectively) but had returned to normal by 1 month after delivery. Pituitary TSH transcript levels and hypothalamic levels of TRH transcripts, however, were similar to those of controls.

Only one of seven dams fed a low-iodine diet for 6 months produced live pups, and these were too few in number to produce significant data. Dams fed a lowiodine diet from 4 months before mating, however, did produce live pups and although they were not significantly lighter than control pups at birth, by 1 month after birth, they were significantly lighter (72 ± 3% of controls). Circulating T3 levels were not significantly different from control at any time point examined. Hypothalamic TRH levels were significantly elevated at birth (451 ± 138% of control), but this difference was not maintained at 1 or 2 months after birth despite the lactating dams being maintained on the low-iodine diet. Pituitary TSH levels showed an upward trend at all time points that reached significance at 1 month after birth (204 ± 19%; P<0·05). Hypothalamic CRH and GRH transcript levels were not different from controls at any time point.

In summary, chronic iodine deficiency or thyroidectomy with low-level T3 replacement in Sprague–Dawley rats markedly impaired fertility and the ability to carry pups to term, and produced an unexpectedly modest up-regulation of the hypothalamo–pituitary–thyroid axis and down-regulation of the hypothalamo–pituitary–adrenal axis.

Journal of Endocrinology (1997) 152, 423–430

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J. R. Seckl and S. L. Lightman

ABSTRACT

Diurnal rhythms in the concentrations of vasopressin (AVP) and oxytocin in cerebrospinal fluid (CSF) differ between species and are unrelated to changes in the levels of these hormones in the peripheral circulation. We have investigated neurohypophysial hormone rhythms in the CSF of the conscious goat by determining whether they are entrained by daily cycles of light and darkness and by assessing the effect of the suppression of plasma cortisol.

Goats were implanted with cisternal cannulae under halothane anaesthesia and allowed to recover. They were accustomed to a 12 h light:12 h darkness lighting cycle (lights on from 07.30 to 19.30 h). After initial serial CSF and plasma sampling the daily cycle of light and darkness was reversed. Three goats were kept in constant light for 8 days before the study and five were given dexamethasone (5 mg/12 h) for 4 days.

There was a significant (P < 0·01) diurnal variation in CSF concentrations of AVP, with a maximum of 3·6 ± 0·8 (s.e.m.) pmol/l at 12.00 h and a minimum of 1·4 ± 0·3 pmol/l at 24.00 h. There were no significant changes in CSF concentrations of oxytocin or plasma AVP. After the light:darkness cycle was reversed the AVP rhythm in the CSF was disrupted after 24 h and reversed after 8 days. The diurnal rhythm of AVP in CSF persisted in animals exposed to constant light. After treatment with dexamethasone plasma cortisol was suppressed and showed no diurnal rhythm but the AVP rhythm in CSF remained unchanged.

J. Endocr. (1987) 114, 477–482

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J. R. Seckl and S. L. Lightman

ABSTRACT

We have investigated the secretion of oxytocin and arginine vasopressin (AVP) during vaginocervical stimulation in the conscious goat and examined the effect of the opioid antagonist naloxone on peptide release to this stimulus. Goats were implanted with guide tubes overlying the cisterna magna under anaesthesia and allowed to recover. Vaginocervical stimulation for 60 s resulted in a marked (P < 0·01) release of oxytocin into the plasma but neither plasma AVP nor cerebrospinal fluid (CSF) concentrations of oxytocin changed significantly.

In a second series of experiments, unoperated goats were infused with saline or naloxone (4 mg bolus + 12 mg/h) in random order on two separate occasions. Infusion of naloxone had no effect on basal plasma concentrations of oxytocin or AVP. There was a marked and significant (P < 0·01) potentiation of oxytocin secretion following vaginocervical stimulation in animals infused with naloxone. Naloxone-infused animals showed a significant (P < 0·01) rise in plasma AVP after stimulation but plasma AVP did not change in the saline-infused controls.

We conclude that vaginocervical stimulation leads to the selective release of oxytocin from the neurohypophysis without affecting concentrations of oxytocin in the CSF. Endogenous opioids inhibit the stimulated secretion of oxytocin and AVP in vivo in response to vaginocervical stimulation in the goat.

J. Endocr. (1987) 115, 317–322

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J. R. Seckl and S. L. Lightman

ABSTRACT

The release of oxytocin into the cerebrospinal fluid (CSF) and plasma of lactating goats was studied following implantation of cisternal and lateral ventricular cannulae. Hand milking was associated with a significant increase in plasma concentrations of oxytocin, but no change in plasma concentrations of vasopressin or CSF concentrations of oxytocin. Intracerebroventricular (i.c.v.) infusion of oxytocin itself (1 pmol/min for 60 min) had no effect on basal plasma levels of oxytocin. It did, however, markedly potentiate the milking-induced increase in plasma oxytocin above the levels achieved during i.c.v. infusion of artificial CSF alone. In the goat, therefore, milking results in a selective release of oxytocin into the plasma, and this release can be potentiated by the presence of increased concentrations of oxytocin in the CSF.

J. Endocr. (1988) 116, 273–277

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D.J.A. Eckland and S.L. Lightman

ABSTRACT

The flow rate of portal plasma was measured during hypothalamo-hypophysial portal sampling in the rat using a modified Worthington-Fink technique. In rats rendered hypothyroid with propylthiouracil, there was a significant 140% increase in portal plasma flow. Median eminence stimulation also increased portal plasma flow by 41%. Orchidectomy and adrenalectomy had no effects on plasma flow. Modification of flow rate in the hypothalamo-hypophysial vascular bed may represent a further mechanism involved in the control of pituitary function.

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M. S. Harbuz, A. Stephanou, N. Sarlis, and S. L. Lightman

ABSTRACT

We have investigated the effects of recombinant human interleukin (IL)-1α, IL-1β and IL-6 on the activation of the hypothalamo-pituitary-adrenal axis. We have determined the effects of a single i.p. injection of cytokine on circulating ACTH and corticosterone levels, corticotrophin-releasing factor (CRF) mRNA in the parvocellular cells of the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary at both 4 h and 24 h after injection. IL-1α had no effect on any of the parameters measured at either time-point. In contrast, IL-1β increased CRF mRNA in the parvocellular paraventricular nucleus and POMC mRNA in the anterior pituitary 4 h after injection. Plasma ACTH and corticosterone were increased at 4 h and circulating ACTH was still increased at 24 h after treatment with IL-1β. IL-6 had no effect on message levels but did increase circulating ACTH and corticosterone levels both 4 h and 24 h after injection. The mechanism responsible for the increase in circulating ACTH after IL-6 injection is unclear but would appear to be different from that which is activated by IL-1β which also results in increased CRF and POMC gene expression.

Journal of Endocrinology (1992) 133, 349–355

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A J Chover-Gonzalez, S L Lightman, and M S Harbuz

Abstract

While the effects of cytokines on the hypothalamo-pituitary-adrenal axis have received a great deal of attention in recent years the effects of cytokines on posterior pituitary hormone release has been less well characterized. In the present study we have investigated the effects of a single i.p. injection of interleukin (IL)-1β on circulating levels of vasopressin (AVP) in the rat. We have found that the ability of IL-1β to increase plasma AVP is strongly influenced by circulating levels of glucocorticoid steroids. IL-1β did not affect plasma AVP in sham-operated control animals over the 4 h period of study. In contrast, following adrenalectomy we were able to stimulate AVP substantially with increases over the 4 h period. This effect was reduced by treatment of adrenalectomized rats with a low dose of dexamethasone and abolished with a high dose. These data suggest an inverse relationship between circulating levels of glucocorticoids and the ability of IL-1β to stimulate plasma AVP.

Journal of Endocrinology (1994) 142, 361–366