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ABSTRACT
We have studied the effect of dopamine together with agonist and antagonist drugs of different specificities on the release of TRH from the perfused, intact hypothalamus of the adult rat in vitro. Dopamine produced a dose-related stimulatory effect on TRH release with maximal effect being achieved at 1 μmol/l (increase over basal, 118 ±16·5 (s.e.m.) fmol TRH; P <0·001 vs basal). This effect was mimicked by the specific D2-agonist drugs bromocriptine (0·1 μmol/l) and LY 171555 (0·1 μmol/l) (increase over basal values, 137·5±13·75 fmol and 158·6± 10·7 fmol respectively; P <0·001 vs basal), but not by the D1-agonist SKF 38393A. The stimulatory effect of dopamine (1 μmol/l) was blocked in a stereospecific manner by the active (d) but not by the inactive (l) isomers of the dopamine antagonist butaclamol. Similar blockade was achieved with the specific D2-antagonist domperidone (0·01 μmol/l) whereas the D1-antagonist SCH 23390 was only effective when used at a concentration 100 times greater. Lower concentrations (0·01 μmol/l) of this D1 -antagonist did not block the stimulatory effect of dopamine. High-performance liquid chromatography characterization of the material secreted within the hypothalamus showed one single peak of immunoreactive material which coeluted with synthetic TRH. These data suggest that dopamine exerts a stimulatory role in the control of hypothalamic TRH release by acting at specific D2-receptors.
J. Endocr. (1987) 115, 419–424
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The main aim of this study was to examine the role of the hypothalamus in controlling the secretion of GH in the ewe. This was evaluated by studying the effect of lesions placed either in the anterior or the posterior medial–basal hypothalamus (MBH) on the concentration of GH in the peripheral circulation during pregnancy and lactation, i.e. when the levels would be high in normal ewes. Simultaneously, the level of prolactin in the peripheral blood of these animals was followed. Lesions of the MBH resulted in a marked decrease in circulating GH as well as disturbances in the mammogenic and lactogenic processes during the periods of periparturition and lactation respectively. The changes were particularly evident if the anterior MBH was lesioned. The present experiments confirm our previous findings that a stimulatory centre is localized in the anterior MBH of sheep whilst in the caudal MBH there is an inhibitory centre regulating the release of prolactin. The results also confirm the important role of GH during lactation in ewes, especially during lactogenesis. The results indicate a differentiated but synchronizing and synergistic role of the MBH regulating the patterns of GH and prolactin secretion in late pregnancy and lactation.
Faculty of Medicine, Center for Health Technology and Services Research (CINTESIS), University of Porto, Porto, Portugal
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, such as food intake and sexual behavior ( Pfaff et al . 2008 , Blaustein 2009 , Liu & Shi 2015 ). One hypothalamic nucleus that plays a preponderant role in these behavioral answers is the ventromedial nucleus of the hypothalamus (VMN), a group of
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Alterations in the concentrations of oestrogen receptors in the uterus, pituitary gland and hypothalamus during the 2 weeks following a single administration of clomiphene citrate (Clomid) to immature, bilaterally ovariectomized rats were investigated. Examination of the uterine wet weight at 1, 7 and 14 days following a single injection of Clomid (100 μg, 250 μg or 10 mg) indicated significant time- and dose-related increments from a control value of 45 ± 2 (s.e.m.) mg to a maximum of 123 ± 3 mg (250 μg dose at 14 days). In contrast, a single injection of oestradiol led to a transient increase in the uterine weight on day 1 to 94 ± 6 mg, but was without effect by days 7 and 14. Analysis of the uterine DNA content 7 and 14 days after treatment with Clomid revealed significant increments from control values of 390 ± 10 μg to a high level of 558 ± 8 μg (10 mg dose at 7 days). There was a transient retention of nuclear oestrogen receptors and rapid replenishment of cytoplasmic oestrogen receptors in less than 24 h in the uteri of animals treated with oestradiol (25 μg), but determinations of receptor content in Clomid-treated animals revealed prolonged retention of nuclear receptors and delayed replenishment of cytoplasmic receptors. The duration and extent of retention of nuclear receptors and depletion of cytoplasmic receptors after treatment with Clomid were found to be dose-dependent. Fourteen days after Clomid treatment, levels of oestrogen receptors in nuclei from the uterus were still raised in all treatment groups, whereas replenishment of cytoplasmic receptors was complete in animals treated with the lower doses (100 and 250 μg) of Clomid.
A single injection of Clomid (250 μg) induced similar prolonged retention of nuclear receptors and delayed depletion of cytoplasmic receptors in pituitary tissue. In contrast, changes in the content of oestrogen receptors in the hypothalamus following Clomid treatment were minimal. The limited effect of Clomid on hypothalamic tissue may mean that the pituitary gland is a more important target for this compound than is the hypothalamus. The findings have confirmed earlier reports on the long-term uterotrophic effect of Clomid and have suggested that under these long-term, in-vivo conditions, Clomid acts in the uterus and pituitary gland as a long-acting oestrogen characterized by prolonged retention of oestrogen receptors in the nucleus and delayed, but otherwise effective, replenishment of the oestrogen receptors in the cytoplasm.
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Action potentials were recorded from 174 neurones in the mediobasal hypothalamus of ovariectomized adult female rats exposed neonatally to monosodium glutamate (MSG) and from 145 neurones in control rats. All of the animals, which were anaesthetized with urethane, had been ovariectomized for at least 3 weeks and received two injections of oestradiol benzoate (20 μg/100 g body weight, i.m.) 72 h and immediately before the recording experiments. The response of each neurone to electrical stimulation of the median eminence and rostral hypothalamus (preoptic and anterior hypothalamic areas; PO/AH) was analysed. The most striking feature of the results obtained was the significant (P < 0·001) loss of inhibitory responses in those neurones remaining in the adult rats after neonatal treatment with MSG. The loss of inhibitory responses applied to both stimulation sites.
In each rat the response of one neurone, which was antidromically identified as projecting to the median eminence, was recorded before and during stimulation of the PO/AH at 50 Hz for 30 s in every min for 15 min. Before and after this stimulation blood was collected from a jugular vein for estimation by radioimmunoassay of concentrations of prolactin and TSH. In the MSG-treated rats significantly (P < 0·05) fewer neurones were inhibited by the 50 Hz stimulation than in control rats. In control rats the plasma concentrations of prolactin nearly quadrupled as an immediate consequence of this treatment, whereas in MSG-treated rats plasma concentrations barely doubled. However, in the MSG-treated rats plasma concentrations of prolactin continued to rise after stimulation ceased, possibly as a consequence of enhanced secretion of thyrotrophin releasing hormone.
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Nucleic acid and protein were assayed in the hypothalamo-hypophysial system of adult Rana esculenta during the annual reproductive cycle.
Adult frogs, weighing 25–35 g, were used and six to seven monthly determinations were made. For each determination material (pars distalis (PD), hypothalamus and cerebral cortex) was collected from five frogs and each pool of material, homogenized in 4 ml cold acetate buffer at pH 5, was analysed in duplicate for RNA, DNA and protein as described earlier (Rastogi & Chieffi, 1972).
In both sexes PD weight, and RNA:DNA and protein:DNA ratios increased during the spawning period (April-June) and thereafter declined (Fig. 1). In fact PD cells accumulated increasing amounts of granules with the approach of spawning and degranulated during July-September (cf. Rastogi & Chieffi, 1970), the latter conforming with decreased PD weight and RNA: DNA and protein: DNA ratios (Fig. 1). The DNA concentration decreased with increasing PD weight and
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To evaluate the role of neuropeptide Y (NPY), a potent appetite stimulant, in controlling food intake and body weight, we investigated the use of antisense oligodeoxynucleotides (ODNs) to inhibit NPY gene expression in the hypothalamus. We compared the hypothalamic distribution of fluorescein-labelled ODNs administered intracerebroventricularly, and effects on food intake and NPY gene expression, of three different structural modifications of an antisense ODN sequence against NPY. Rats had either the antisense or missense ODNs (24 micrograms/day) or saline infused into the third ventricle by osmotic minipumps for 7 days. The unmodified phosphodiester ODN was not detectable in the hypothalamus after 7 days and had no effects on food intake. The phosphorothioate ODN was widely distributed throughout the hypothalamus but had nonselective effects, with similar changes in food intake and NPY mRNA levels in the antisense and missense groups, and was severely toxic. The propyl-protected ODN appeared to penetrate the hypothalamus well but had no antisense-selective effects on NPY mRNA levels or food intake. Antisense ODNs are increasingly used to inhibit gene expression in vitro and in intact animals. These negative findings underline the need for rigorous evaluation of any effects of antisense ODNs administered into the central nervous system, and raise doubts about the validity of this approach in physiological or pharmacological studies.
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ABSTRACT
The plasma of normal man and the rat, and an acetone extract of hypothalamus from the rat, have an ability to inhibit Na-K-ATPase which is related directly to salt intake. The ability of the plasma to inhibit Na-K-ATPase is raised in essential hypertension.
The ability of plasma and of an acetone extract of hypothalamus from six spontaneously hypertensive (SHR) rats and six normotensive control (WKY) rats to inhibit Na-K-ATPase of fresh guinea-pig kidney was studied using cytochemical bioassay techniques. With a validated assay, which measures the capacity of biological samples to stimulate glucose-6-phosphate dehydrogenase (G6PD) as an index of their capacity to inhibit Na-K-ATPase, the mean G6PD-stimulating ability of the plasma from the SHR and the WKY rat was 772·3 ± 48·1 units/ml and 12·5 ± 2·6 units/ml respectively (P < 0·01) and of the hypothalamic extracts it was 2·2 ± 1·7 × 108 and 4·5 ± 1·8 × 104 units/hypothalamus (P < 0·01). With a semi-quantitative cytochemical assay, which measures Na-K-ATPase activity directly, plasma and an acetone extract of hypothalamus from the spontaneously hypertensive rat had much greater capacities to inhibit Na-K-ATPase than plasma and extract from the WKY rat.
These raised levels of Na-K-ATPase inhibitory activity in the plasma of the SHR rat are similar to the highest values found in the plasma of patients with essential hypertension. The results suggest that the substance responsible for the increased capacity of the plasma to inhibit Na-K-ATPase may originate from the hypothalamus and that it may, in part, be involved in the mechanisms which induce the rise of arterial pressure in inherited forms of hypertension.
J. Endocr. (1986) 108, 69–73
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Gsk3 β has been shown to be increased in HF-fed and HF/high-fructose-fed mice ( Benzler et al . 2012 , Anderson et al . 2013 ), whereas overexpression in the mediobasal hypothalamus has been shown to lead to hyperphagia and obesity in mice that
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ABSTRACT
Prostaglandin (PG) and thromboxane (TX) synthesis by homogenates of the hypothalamus of rats has been measured in relation to the preovulatory surge of LH. Prostaglandin and TX production by the median eminence (ME) was five to ten times higher than that by the anterior hypothalamus/preoptic area (AH-POA). Prostaglandin E2 and PGF2α were the major prostaglandins synthesized by the ME and AH-POA respectively. During the 4-day oestrous cycle, the PG-and TX-synthesizing capacity of the ME showed daily changes, being high at 06.00 and 22.00 h and, with the exception of pro-oestrus, low at 18.00 h. There was an additional peak of PGE2 production by the ME at 18.00 h on pro-oestrus coincident with the preovulatory LH surge. Progesterone treatment stimulated PGE2 synthesis by the ME of long-term ovariectomized, oestradiol-primed rats but not by the ME of acutely ovariectomized, oestradiol-primed rats. 2-Hydroxyoestradiol had no effect on PG and TX production by the ME at 18.00 h on dioestrus or 18.00 h on pro-oestrus. Noradrenaline stimulated PG and TX synthesis by the ME at the former time but not at the latter time.
Prostaglandin F2α-synthesizing capacity of the AH-POA peaked at 22.00 h on each day of the 4-day cycle. There was also an additional peak at 14.00 h on each day except dioestrus. Similar peaks occurred in the production of PGE2 and TXB2, except on pro-oestrus when the production of each compound remained low. There was no association between increased PGE2 production by the AH-POA and the preovulatory surge of LH. Noradrenaline, but not 2-hydroxy-oestradiol, stimulated PG and TX production by the AH-POA at 18.00 h on both dioestrus and pro-oestrus. Progesterone stimulated PGE2, PGF2α and 6-oxo-PGF1α production by the AH-POA of acute, ovariectomized, oestradiol-primed rats but not of long-term ovariectomized, oestradiol-primed rats.
Flurbiprofen, a cyclo-oxygenase inhibitor, prevented the preovulatory LH surge in two rats and delayed the LH surge by 2 h in four rats. It also reduced PG and TX production by the ME and AH-POA. Overall, the present studies show that there is an increase in PGE2-synthesizing capacity of the ME at the time of the preovulatory LH surge in the rat, and that the administration of an inhibitor of prostaglandin synthesis interferes with the timing of the LH surge.
J. Endocr. (1984) 103, 155–164
