Opiate-thyroid hormone interactions in the regulation of thyrotropin secretion in the rat

Studies were performed to determine the role of thyroid hormone in the suppression of thyrotropin (TSH) by opiates. Serum samples were collected by decapitation 1, 3, 6, 12, 24, or 48 h after rats were implanted with 1 sustained-release morphine (75 mg) or placebo pellet. Morphine decreased TSH by 44% at 1 h and by 83% at 3 h, and TSH remained significantly depressed by 38% through 48 h. Thyroxine (T4) levels were significantly reduced from 12 to 24 h after morphine, but triiodothyronine (T3) levels were not affected. When control or thyroidectomized (THX) rats were implanted with morphine or placebo 24 h before serum collection, morphine significantly decreased TSH, T3 and T4 in controls but had no effect on TSH in THX rats. Thus, it appears that the morphine-induced suppression of TSH release requires circulating thyroid hormone. When THX rats were chronically treated with morphine or placebo, then injected subcutaneously with saline or 1, 10 or 100 micrograms T4/kg body weight 24 h prior to serum collection, morphine treatment alone did not affect TSH in THX rats. T4 replacement caused a dose-dependent decrease in serum TSH in both morphine and placebo rats; however, TSH was suppressed significantly more in morphine than in placebo rats. Thus, while chronic morphine treatment is ineffective in suppressing in TSH in THX rats, morphine interacts with thyroid hormone to reduce TSH release. These data suggest that morphine may exert its inhibitory effect on TSH secretion by increasing the negative feedback sensitivity to thyroid hormones.     

The autocrine/paracrine regulation of thyrotropin secretion.

Peptides originally described in other tissues have been located in the anterior pituitary gland. Detection of their encoding mRNAs and specific receptors, together with demonstration of peptide local action led to the postulation of the existence of a paracrine/autocrine regulation of pituitary function. Direct evidence for the role of endogenous peptides has come from studies aiming to block their action through immunoneutralization or pharmacologic blockade. Here we review evidence of pituitary produced peptides as potential candidates as local regulators of thyrotropin secretion. Few studies have approached the subject and most data are not conclusive. Until now, the most consistent data relate to neuromedin B, a bombesin-like peptide. The combined observation of high peptide concentration in rat thyrotrophs, the ability of the exogenous peptide to inhibit thyrotropin (TSH) release in physiologic doses plus the effect of the specific neuromedin B antiserum to increase basal TSH release from isolated pituitaries suggest that neuromedin B acts as a constitutive autocrine TSH-release inhibitor. Neuromedin B is upregulated by thyroid hormones and downregulated by thyrotropin-releasing hormone (TRH) that is consistent with proposed role of local factors, namely to partially mediate or modulate the effects of hormones on pituitary function. However, future studies will certainly confirm other candidates as local regulators of TSH secretion, as well as their relevance at physiologic and pathologic conditions.     

Kinesin is involved in regulation of rat pancreatic amylase secretion

BACKGROUND & AIMS: Kinesin has recently been localized to zymogen granules of pancreatic acini and is suggested to participate in exocytosis of exocrine pancreas. We examined the function of kinesin in regulated exocytosis of pancreatic acini in this study. METHODS: Kinesin function in exocytosis was examined by introducing hexahistidine-tagged recombinant kinesin protein and antikinesin monoclonal antibody into streptolysin-O-permeabilized acini. Intracellular localization of introduced recombinant kinesin was investigated by immunohistochemistry. Interaction between recombinant kinesin and the microtubule network was confirmed by nocodazole pretreatment of acini. Kinesin regulation by secretagogues was investigated by examining their effect on adenosine triphosphatase (ATPase) activity of endogenous kinesin. RESULTS: Recombinant kinesin enhanced calcium-stimulated amylase release from streptolysin-O-permeabilized acini. Introduced recombinant kinesin was localized to both the microtubule network and zymogen granule. Nocodazole pretreatment of acini abolished the enhancing effect of recombinant kinesin on calcium-stimulated amylase release. Antikinesin antibody inhibited amylase release stimulated by the combination of calcium and cyclic adenosine monophosphate (cAMP) but not that stimulated by calcium alone. Secretin and 8-bromo-cAMP increased ATPase activity of endogenous kinesin. CONCLUSIONS: Kinesin plays a stimulatory role in regulated exocytosis of pancreatic acini and is involved in stimulus-secretion coupling through a cAMP-dependent pathway.     

Beta- and alpha-adrenergic mechanisms are involved in regulation of rat pineal type II thyroxine 5'-deiodinase activity during development.

Adrenergic regulation of type II T4 5'-deiodinase (5'-D) activity has been studied in the rat pineal gland during development. Nocturnal increases in 5'-D activity gradually rose from the second week of age until the sixth week. Isoproterenol, a beta-adrenergic agonist, stimulated 5'-D activity during the daytime; however, the pattern of stimulation during development was slightly different from nocturnal activation of the enzyme, since pineal 5'-D activity could be clearly activated by isoproterenol from the first week of age. Isoproterenol activation of the enzyme always reached more than 70% of nocturnal values at all ages studied. Phenylephrine, an alpha-adrenergic agonist, did not increase the enzyme activity. Another selective alpha-adrenergic agonist, methoxamine, as well as clonidine, an alpha 2-adrenergic agonist, were ineffective in stimulating the enzyme, while norepinephrine or terbutaline, a beta-adrenergic agonist, clearly activated it. Additional results showing a role for alpha-adrenergic receptors on pineal 5-D activity were obtained when alpha- and beta-adrenergic receptor blockers were used. Thus, propranolol, a beta-adrenergic blocker, clearly prevented pineal 5'-D activation in both 2- and 6-week-old rats when the gland was stimulated by either norepinephrine or darkness at night. However, prazosin, a selective alpha 1-adrenergic receptor blocker, also prevented the norepinephrine-induced or darkness-induced activation of the enzyme in 2-week-old rats, although it was ineffective when used in 6-week-old rats. Moreover, at night and after 3 h of exposure to darkness, phenylephrine was able to activate the enzyme. Results strongly suggest a role for alpha-adrenergic receptors, in addition to beta-adrenergic receptors, in regulating rat pineal 5'-D activity during development.     

Possible mechanisms involved in growth hormone secretion induced by galanin in the rat

The mechanisms by which central or systemic administration of galanin stimulates GH secretion were investigated in either conscious or urethane-anesthetized male rats. Intracerebroventricular injection of synthetic porcine galanin, a 29-amino acid gut-brain peptide (0.12, 0.6, and 3 nmol/rat), resulted in a dose-related increase in plasma GH. The plasma GH level was increased by an N-terminal galanin fragment [galanin-(1-19)], but not by C-terminal fragments [galanin-(2-29) and -(21-29)]. Intravenous injection or infusion of galanin (0.6 and 3 nmol/100 g BW) also raised plasma GH. The plasma GH increase induced by galanin was inhibited by pretreatment with rabbit antiserum specific for rat GRF. Pretreatment with yohimbine or phenoxybenzamine, alpha-adrenergic blockers, or picrotoxin, a gamma-aminobutyric acid (GABA) antagonist, blunted the plasma GH increase induced by intracerebroventricular injection of galanin. On the other hand, the plasma GH increase induced by iv injection of galanin was suppressed by picrotoxin, but not by phenoxybenzamine. These findings suggest that 1) both central and systemic administration of galanin stimulate GH secretion in the rat; 2) the N-terminal structure of galanin is required to stimulate GH secretion; 3) the stimulating effect of galanin is mediated, at least in part, by hypothalamic GRF; and 4) central alpha-adrenergic and GABAergic mechanisms may be involved in GH release induced by central administration of galanin, whereas systemic injection of galanin stimulates GH release predominantly through GABAergic mechanisms in the rat.     

Thyroid hormone feedback regulation of the secretion of bioactive thyrotropin in the frog.

Thyrotropin-releasing hormone (TRH), ovine corticotropin-releasing hormone (oCRH) (both 268 nM), and mammalian gonadotropin-releasing hormone (mGnRH) (268 and 2680 nM) stimulated the secretion of bioactive thyrotropin (TSH) by Rana esculenta pituitaries (pars distalis) in vitro. Preincubation of the pituitaries with 50 ng/ml (64 nM) thyroxine (T4) for 6 hr suppressed the TRH- and oCRH-induced (268 nM) secretion of bioactive TSH, but did not affect the response of the pituitaries to 268 nM mGnRH. Triiodothyronine (T3) (64 nM) reduced both the TRH- and mGnRH-stimulated release of bioactive TSH; the response of TSH to TRH even decreased toward basal levels while a significant TSH response to mGnRH remained. In a separate experiment, pituitaries were preincubated for 6 hr with different equimolar doses of T3 and T4 (6.4, 32, and 64 nM); neither treatment affected the mGnRH-stimulated secretion of bioactive TSH. On the other hand, T4 suppressed the TSH response to TRH in a dose-dependent manner. The inhibitory effects of thyroid hormones on the TRH-induced release of bioactive TSH was present for at least 4 hr after their removal from the incubation medium. These results suggest that thyroid hormones exert a negative feedback control on the secretion of bioactive TSH in adult frogs by a direct action on the pars distalis. There may also be differences in thyroid hormone sensitivities of the TSH responses to mGnRH and TRH.     

Biochemical mechanisms involved in monomethyl succinate-induced insulin secretion.

Esters of succinic acid stimulate insulin secretion from pancreatic beta-cells. Using collagenase-isolated rat islets, the transduction mechanisms involved were investigated. In freshly isolated perifused islets, monomethyl succinate (MMSucc), in the presence of basal (2.75 mM) glucose, stimulated insulin release in a biphasic pattern. This secretory response was dependent on extracellular calcium movement into the beta-cell, since the calcium channel blocker nitrendipine (5 microM) abolished it. The glucokinase inhibitor mannoheptulose (20 mM) had no effect on its secretory action, while the protein kinase-C inhibitor staurosporine (20 nM) reduced secretion to MMSucc. In addition, while ineffective alone, the diacylglycerol kinase inhibitor monooleoylglycerol (25 microM) potentiated MMSucc-induced insulin release. A similarly amplified response occurred in the presence of forskolin (0.25 microM), a compound that elevates islet cAMP levels. The sodium salt of succinic acid (20 mM) had no effect on insulin release in the presence or absence of forskolin. Prior treatment with MMSucc in the presence of 2.75 mM glucose sensitized islets to the usually weak insulin secretory effect of 7.5 mM glucose. Other groups of islets were incubated for 2 h with myo-[2-3H]inositol to label their phosphoinositide pools. These islets were subsequently stimulated, and the kinetics of [3H]inositol efflux and insulin secretion were measured. MMSucc induced a rapid and sustained dose-dependent increase in [3H]inositol efflux rates. In batch-incubated islets, MMSucc increased inositol phosphate levels. Finally, MMSucc (20 mM), in the presence of 8 mM glucose, did not influence the detritiation of [5-3H]glucose, but reduced the oxidation of [U-14C] glucose. These results support the following conclusions. First, MMSucc is a potent activator of islet phosphoinositide hydrolysis. Second, the activation of protein kinase-C appears to contribute to the acute insulin secretory effect of MMSucc. Third, MMSucc-induced increases in phosphoinositide hydrolysis contribute at least in part to its ability to acutely stimulate insulin release and prime the beta-cell to subsequent stimulation. Finally, mitochondrial events associated with the oxidative metabolism of MMSucc may underlie its insulinotropic action.     

Characterization of ion transport mechanisms involved in bombesin-stimulated biliary secretion in rat cholangiocytes

BACKGROUND/AIMS: Bombesin is a neuropeptide which stimulates fluid and bicarbonate secretion from cholangiocytes by stimulating Cl-/HCO3- exchange. However, the underlying regulation and interactions of ion transporters and channels mediating this bombesin-stimulated biliary secretion are not well characterized. The aim of the study was to characterize the ion transport processes involved in bombesin-stimulated secretion in polarized cholangiocytes in comparison with those of secretin. METHODS: Isolated bile duct units (IBDU) were prepared from normal rat liver. Biliary secretion induced by bombesin was measured by quantitative video-microscopy in the presence and absence of inhibitors. RESULTS: Bombesin-stimulated secretion was inhibited by H2-DIDS, NPPB, BaCl2, TEA, and acetazolamide. However, in contrast to secretin, bombesin-stimulated secretion was not inhibited by disruption of microtubules. CONCLUSIONS: Bombesin-stimulated biliary secretion is dependent on anion exchangers, Cl- and K+ channels, and carbonic anhydrase but not on microtubules. Bombesin regulates secretion in cholangiocytes by different mechanisms from those established for secretin.     

Influence of prolonged glucocorticoid treatment on intracellular mechanisms involved in ACTH secretion in the rat

Two chemically characterized peptides, arginine vasopressin (AVP) and corticotrophin-releasing factor-41 (CRF-41), known to stimulate ACTH secretion by interaction with their respective specific receptors on the corticotroph, were shown to cause the accumulation of phosphate esters of inositol (IP) and adenosine 3',5'-monophosphate (cAMP) respectively when added to rat anterior pituitary fragments incubated in vitro. The former 'second messenger' response (IP production) was unaffected in tissues removed from animals treated with prednisolone in the drinking water (1035 mumol/1) for 14 days. On the other hand, the cAMP response, whilst still present, was inhibited by some 50% in tissues taken from such animals. In contrast, pituitary glands from steroid-treated rats failed to respond to challenge with a variety of substances expected to cause the release of ACTH by mimicking or provoking the production of IP or cAMP. Indeed, of the wide range of ACTH secretagogues tested, only the phospholipase A2 activator melittin was able to cause attenuated ACTH release from tissues removed from treated rats. The failure to provoke ACTH release from tissues removed from steroid-treated animals was also seen when submaximal concentrations of CRF-41 or AVP, or hypothalamic extract or 48 mmol K+/1 were used as the stimuli. The staged recovery of the ACTH secretory response and IP and cAMP accumulation in vitro following the withdrawal of prednisolone treatment was also investigated. A cAMP response that did not differ significantly from that of control tissue and a normal ACTH response to K+ and to melittin were all recovered by 3 days after withdrawal, and the response to cholera toxin showed a partial recovery. Responses to all stimuli of ACTH secretion which cause their effect by entering the corticotrophs were normal by 5 days after withdrawal, when the response to CRF-41 was still significantly, and that to AVP still slightly, reduced compared with controls. Surprisingly, restoration of the ACTH response was most delayed when the expectedly most potent extracellular stimulus (hypothalamic extract) was used. In this case, release was still significantly impaired 7 days after steroid withdrawal. The results show that the glucocorticoid acts to compromise several distinct steps in the process whereby extracellular signals such as CRF-41 and AVP cause the secretion of ACTH. The only step that appears to be spared is the generation of IP by AVP.(ABSTRACT TRUNCATED AT 400 WORDS)     

Sex steroids modulate the pituitary parameters involved in the regulation of TSH secretion in the rat

The sex-related differences observed in the regulation of TSH secretion was further investigated by determination of the densities of T3 nuclear and TRH membrane receptors as well as the activity of 5'-deiodinase (5'D) in the anterior pituitary gland of adult male and female rats. The respective modulatory roles of androgens and estrogens on these parameters were evaluated by similar determinations carried out in castrated and in estrogen-treated male rats. The density of pituitary T3 and TRH receptors and the activity of 5'D type II were significantly greater in the female than in the male rats. The E2-treated male rats disclosed a female profile, viz. also greater densities of T3 and TRH receptors when compared with control male rats (2.3 +/- 0.2 vs 1.8 +/- 0.2 fmol T3/mg gland and 9.4 +/- 0.8 vs 6.0 +/- 0.8 fmol TRH/mg gland, mean +/- SEM), whereas no changes were found in the castrated rats. The E2-treated rats and the castrated rats exhibited an increased pituitary activity of 5'D, type II (0.87 +/- 0.10 and 0.66 +/- 0.05, respectively, vs control 0.34 +/- 0.07 pmol rT3.h-1.(mg protein)-1), suggestive of a stimulatory effect of E2 and of an inhibitory effect of androgens on this parameter. In contrast, no differences in hepatic 5'D were found between all groups, illustrating the well-known tissue-specific regulation of 5'D. These results demonstrate that the sex difference in the density of pituitary T3 and TRH receptors and the activity of 5'D in the adult rat is mainly due to a modulatory effect of estrogens, which may be responsible for the sex-dependent regulation of TSH secretion.     

Suppression of prolactin and thyrotropin secretion in the rat by antiserum to thyrotropin-releasing hormone.

Administration of antiserum to synthetic thyrotropin-releasing hormone (TRH) to male and female rats cause a 50% and a 70% suppression in serum levels of prolactin and thyrotropin, respectively, as compared with controls injected with normal rabbit serum. The degree of suppression was similar in diestrous and proestrous female rats and in male rats. These findings support the view that, in addition to its original designation, TRH also has a physiological role in regulating release of pituitary prolactin.     

Evidence for a role of alpha-adrenergic mechanisms in regulation of episodic growth hormone secretion in the rat.

The role of catecholamines in regulation of episodic GH secretion was investigated in the male rat. Administration of alpha-methyl-p-tyrosine (alpha-MT; 250 mg/kg ip) caused significant suppression of GH bursts and resulted in marked elevation of plasma PRL. Intravenous administration of apomorphine (.03 and .1 mg/kg) had no effect on decreased GH levels, whereas clonidine (150 micrograms/kg) restored GH secretion. Apomorphine significantly reduced PRL levels in alpha-MT-treated rats whereas, clonidine resulted in a further increase in PRL.     

Somatostatin is a regulator of thyrotropin secretion in the perinatal rat

The perinatal rat exhibits low serum TSH levels in the presence of very low concentrations of T3 and T4. We had reported previously that this animal does not require endogenous TRH for TSH release. We investigated here whether the inhibitory hormone somatostatin (SS) has a role in maintaining the low TSH secretory set-point. To study the effect of SS in the immature model, we passively immunized pregnant rats with SS antiserum to neutralize endogenous SS. Acute iv administration of 0.3 ml SS antiserum to pregnant rats (day 20 of pregnancy) resulted in a significant serum TSH elevation in both mother and fetus 60 min after injection compared to the control values [maternal TSH, 62 +/- 6 muU/ml vs. control, 43 +/- 4 (mean +/- SE; P less than 0.05); fetal TSH, 95 +/- 8 vs. control, 66 +/- 6 (P less than 0.02)]. The binding capacity of the AS in the fetal serum far exceeded the circulating SS in the fetus. Similar results were obtained when neonates 5 and 10 days of age were injected with 0.1 ml AS, ip. Further experiments were done with the use of synthetic SS. Acute iv injection of synthetic synthetic SS (1 microgram) to pregnant rats made hypothyroid by feeding of a low iodine-propylthiouracil diet for the last week of gestation suppressed the elevated serum TSH level in both mother and fetus 15 min after the injection [maternal TSH, 102 +/- 11 vs. control, 163 +/- 22 (P less than 0.05); fetal TSH, 99 +/- 9 vs. control, 143 +/- 13 (P less than 0.02)]. Similar results were obtained when hypothyroid neonates 5 and 10 days of age were injected with 1 microgram SS, ip. These findings suggest that there is similarity in the effects of SS on TSH secretion (suppression) in mother, fetus, and neonate and dependence of the perinatal TSH on SS, in contrast to TRH. It is, then, likely that TSH secretion in the perinatal rat is under the inhibitory influence of endogenous SS.     

Abnormal thyrotropin and prolactin levels in untreated corticotropin deficiency

A patient with isolated corticotropin deficiency demonstrated hyperresponsiveness of both thyrotropin and prolactin after protirelin stimulation. Following glucocorticoid replacement therapy, responses decreased to normal. Since true primary hypothyroidism may occur in association with cortisol-deficient states, it is necessary to reserve final evaluation until after glucocorticoid replacement. The finding of combined thyrotropin and prolactin hyperresponsiveness to protirelin suggests a related glucocorticoid feedback function.     

The role of central noradrenergic neurons in the control of thyrotropin secretion in the rat.

To investigate the role played by hypothalamic noradrenaline (NE) in the regulation of TRH-TSH release during tonic and cold activated conditions, drugs and surgical procedures able to interfere with central NE tonus were utilized. The time course of the effect of alpha-methyl-para-tyrosine (alpha-MpT) on basal TSH secretion was followed. The tyrosine hydroxylase (TH) inhibitor was unable to modify TSH plasma levels, whereas NE hypothalamic content decreased beginning with the third hour. The acute release of TSH evoked by cold exposure (CE) was prevented by pretreatment with alpha-MpT 1 h before; when alpha-MpT was followed 40 min later by clonidine, a central noradrenergic stimulating agent, TSH response to cold, previously blocked by the TH inhibitor was restored. Intraventricular injection of 10 micrograms of clonidine hydrochloride in unstimulated rats caused a significant rise of basal TSH levels 3, but not 10 min after the administration. Complex deafferentation of the medial basal hypothalamus (MBH), which destroys all the NE fibers afferent to this area, caused no change of thyrotropin secretion in basal conditions. Deafferented animals did not show any acute increase of TSH in response to CE. The results of this study provide evidence that NE may be the catecholamine (CA) mediating the rise in TSH following CE and that the direct stimulation of central NE receptors can evoke a massive TSH release from the anterior pituitary gland also in basal conditions.     

Different gamma-aminobutyric acid receptor subtypes are involved in the regulation of opiate-dependent and independent luteinizing hormone-releasing hormone secretion

The neurotransmitter gamma-aminobutyric acid (GABA) appears to be involved in the control of gonadotropin secretion. These studies were conducted 1) to evaluate the effect of GABAergic drugs on in vitro LHRH secretion and 2) to characterize the role of different types of GABA receptors (the GABA-A and GABA-B subtypes) in these actions. Arcuate nuclei-median eminence fragments were incubated in vitro, and the release of LHRH, prostaglandin E2 (PGE2), arginine vasopressin, and oxytocin was measured by RIA. Both GABA and muscimol at different concentrations induced an increase in LHRH release, but did not affect the release of arginine vasopressin and oxytocin. This stimulatory effect was blocked by the specific GABA antagonist bicuculline, suggesting the involvement of GABA-A type receptors. Muscimol-stimulated LHRH release was not affected by the presence of phentolamine, suggesting that the stimulatory effect of GABA-A receptors on LHRH release is not mediated by interactions with the noradrenergic system. PGE2 has been shown to be a potent secretagogue of LHRH from the median eminence in vitro, and in this model the stimulatory effect of PGE2 was enhanced by muscimol. Baclofen, a specific GABA-B type receptor agonist, had no effect on basal LHRH release, but completely suppressed naloxone-stimulated LHRH and PGE2 secretion. The inhibitory effect of baclofen was blocked by the presence of 5-aminovalerate, a drug that has been shown to block the inhibitory effect of baclofen on NE release from noradrenergic terminals. This suggests the possibility that GABA-B receptors interacting with noradrenergic terminals may be responsible for the inhibitory effect of baclofen on naloxone stimulation. This study uncovered both stimulatory and inhibitory effects of GABA on LHRH release after activation of GABA-A or GABA-B receptors, respectively. Further, the data show possible relationships among the GABAergic, endogenous opiate peptide, and noradrenergic systems in the control of LHRH release from the hypothalamus.     

Physiological regulation of circadian and pulsatile thyrotropin secretion in normal man and woman

The circadian and pulsatile TSH secretion profiles were investigated in 5 females at the time of menstruation and 21 healthy males by sampling blood every 10 min for 24 h. Computer-assisted analysis, i.e. the Cluster and Desade programs, revealed means of 9.9 +/- 1.7 (Cluster) and 11.4 +/- 3.9 (Desade) pulses/24 h. More than 50% of the TSH pulses were detected between 2000-0400 h. Male and female subjects showed no significant difference in the basal mean and pulsatile secretion of TSH or in the TSH response to TRH (200 micrograms). Repetition of the TSH secretion analysis in 4 healthy subjects after 1, 2, and 6 months (2 subjects) revealed a significantly better cross-correlation within than between individuals (P less than 0.0001). We modulate the circadian TSH secretion pattern by acute sleep withdrawal or prolonged sleep after a night of sleep withdrawal in six healthy male volunteers. Sleep withdrawal augmented the nightly TSH secretion (mean serum TSH, 2.1 +/- 1.3 mU/L; mean TSH in sleep, 1.3 +/- 0.5 mU/L; P less than 0.05), whereas sleep after sleep withdrawal almost completely suppressed the circadian variation (mean TSH, 1.1 +/- 0.7 mU/L; P less than 0.01). This modulation is due to a significant decrease in pulse amplitude, but not to an alteration in the frequency or temporal distribution of TSH pulses.     

Effect of dexamethasone on the secretion of thyrotropin in the rat: dose and time relations.

Serum TSH and corticosterone concentrations were measured in intact rats and in rats given TRH or exposed to short-term cold 3 h and 12 h after pretreatment with dexamethasone in various doses. Dexamethasone given 3 h before experiemtns significantly depressed both TRH- and cold-induced TSH responses at all dose levels. Dose of 25 pg/100 g body weight significantly depressed serum TSH concentration when given 3 h before the experiment. However, when given 12 h before the experiment the drug augmented TRH-induced TSH secretion, although the cold response was unaltered. In intact rats dexamethasone significantly depressed serum TSH concentration in doses of 250 and 500 mug/100 g body weight. In all experiments the steroid blocked ACTH secretion. These results support the view that the effect of dexamethasone on thyroid function is highly dependent on the time relations. A single large dose of dexamethasone has first an inhibitory effect at the pituitary level and then facilitates pituitary to TRH and at the same time inhibits secretion of TRH in response to cold.     

The effects of cysteamine on thyrotropin and immunoreactive beta-endorphin secretion in the rat

We examined the effects of the thiol agent cysteamine (CSH), which is known to deplete the hypothalamus of immunoreactive somatostatin, on physiological TSH and beta- endorphin secretion in the adult male rat. CSH at doses of 90 and 300 mg/kg CSH produced a rapid decline in plasma TSH, whereas a dose of 30 mg/kg did not alter plasma TSH levels. After the higher doses of CSH, TSH levels in the blood remained lower than control values on day 2, but returned to normal by 1 week. This decrease in TSH within the plasma was not associated with a reduction in hypothalamic TRH concentrations. The TSH response to 500 ng/kg TRH was normal in CSH-treated animals. Blockade of norepinephrine synthesis with diethyldithiocarbamate (500 mg/kg) or fusaric acid (100 mg/kg) inhibited TSH secretion in a manner similar to that of CSH. beta-Endorphin-like immunoreactivity (bet-End-LI) was elevated in the plasma immediately after CSH (300 mg/kg) administration. This was associated with a 58% reduction in anterior pituitary beta-End-LI and no change in hypothalmic beta-End-LI. Plasma beta-End-LI returned to normal on day 2. The increase in plasma beta-End-LI induced by immobilization stress was not compromised by CSH treatment. The observed effects of CSH on both TSH and beta-End-LI are consistent with a reduction in central norepinephrine neurotransmission through the known actin of CSH to inhibit dopamine-beta-hydroxylase. Acute stress may play a role as well in the observed changes in TSH and beta-End-LI secretion.