Changes in neurotransmitter receptor expression levels in rat brain after 4-week exposure to 1-bromopropane
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Neurotoxicity
Pons
Dopamine, secreted by the median eminence into hypophysial stalk blood, accounts for much of the inhibition of PRL release known to be exerted by the hypothalamus, and recent studies of lactating rats have revealed a brief decrease (60–70% for 3–5 min) in hypophysial stalk plasma dopamine concentrations immediately after the onset of a simulated suckling stimulus (electrical stimulation of a mammary nerve trunk). In the present study, we investigated the regulatory significance of this decrease for the increased PRL secretion evoked by this stimulus and, in addition, researched the effect of TRH on plasma PRL levels when it was administered before and after the decrease in dopamine. Control lactating rats anesthetized with urethane exhibited low and unvarying levels of plasma PRL (mean ± SEM 3.5 ± 0.6 ng/ml). Intraperitoneal injection of αmethyl- p-tyrosine (AMPT) resulted in a 120-fold elevation of plasma PRL levels. Dopamine infusions (1.0 μg-min/kg BW) into AMPT-treated rats, achieving stalk plasma dopamine concentrations in the range normally found there (8.4 ± 1.6 ng/ml), suppressed plasma PRL levels by 67%. However, a brief decrease (70% for 5 min) in the dopamine infusion rate to mimic the pattern of dopamine secretion in hypophysial stalk blood after a simulated suckling stimulus did not alter plasma PRL concentrations. TRH injection (300 ng/kg BW, iv) failed to acutely increase plasma PRL levels in control rats with low basal levels of plasma PRL, in AMPT-treated rats with high basal PRL levels, or in AMPT-treated dopamine-infused rats exhibiting intermediate plasma PRL levels; however, it did so in rats undergoing a 5-min 70% decrease in the rate of dopamine infusion. The magnitude of the increase was about 3-fold and lasted for 20–30 min. These results suggest that the brief decrease in dopamine secretion evoked by suckling does not, by itself, increase PRL secretion. However, it may condition the pituitary to respond to a putative PRL-releasing factor (TRH). Thus, these results suggest that the increased PRL secretion after suckling is due to a decrease in the secretion of dopamine and an increase in the secretion of a PRL-releasing factor.
Median eminence
Pituitary stalk
Basal (medicine)
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The obese Zucker rat is a model of youth-onset obesity associated with hyperphagia. In this study, dehydroepiandrosterone's effect at decreasing food intake and body weight in the obese Zucker rat was investigated. Rats were treated with a dehydroepiandrosterone-supplemented diet (0.0, 0.06, 0.15, 0.3, or 0.6%) for 7 days. The 0.3 and 0.6% treatment groups showed a dramatic decrease in daily food intake, which was evident the 1st day. In addition to the reduction in food intake, body weight changes also were affected significantly in the high-dose treatment groups. The possibility that these dehydroepiandrosterone-induced changes were correlated to perturbations in central neurotransmitter levels associated with appetite control was investigated. The hypothalamus, frontal cortex, striatum, and hippocampus of dehydroepiandrosterone-treated animals were assayed for neurotransmitters known to have inhibitory or stimulatory effects on feeding behavior (serotonin, dopamine, norepinephrine, and epinephrine). Significant differences from steroid-free controls were noted only in the levels of hypothalamic serotonin in animals treated with dehydroepiandrosterone. Serotonin in the hypothalamus has been shown to decrease feeding behavior. The magnitude of dehydroepiandrosterone's effect on hypothalamic serotonin correlated with its effect on feeding behavior. Thus, dehydroepiandrosterone may reduce hyperphagia by altering hypothalamic levels of serotonin.
Dexfenfluramine
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The pituitary regulation of the sexually differentiated PRL receptor in rat liver was studied. PRL receptors were measured in a crude membrane fraction (105,000 × g pellet) using [125I]iodohuman PRL as tracer. Human GH (hGH), continuously administered by Alzet osmotic minipumps with an infusion rate of 5 μg/h for 1 week, was shown to induce PRL receptors in livers from male and female hypophysectomized-gonadectomized rats. The PRL receptors were increased to a level found in control female rat livers. This inductive effect of hGH was also seen in adrenalectomized and thyroidectomized male rats. In intact male rats given hGH, PRL receptors were increased to a female level in 4–7 days. hGH was effective in doses of 2.5 and 5 Μg/μl in inducing a female receptor pattern. The induced PRL receptors in male rats had characteristics similar to those of hepatic PRL receptors in female rats when data were calculated according to Scatchard (Kd = 0.13 × 10-9vs. 0.15 × 10-9 M; number of binding sites 88 vs. 57 fmol/mg protein). Also, the endogenous rat hormones, rat PRL (rPRL) and rat GH (rGH), were administered by minipumps to hypophysectomized male rats. With the infusion rate used (10 μg/h), rPRL had no effect, whereas rGH (NIAMDD-B6) increased PRL receptor levels to approximately 37% of the female control level. A more complete induction of PRL receptors (75% of the female control levels) in hypophysectomized males was achieved using another preparation of rGH (NIAMDD 1-4). Also, in hypophysectomized female rats, rPRL was ineffective in inducing PRL receptors. On the other hand, ovine PRL was found to give a partial restoration of PRL receptors in hypophysectomized female rats. The results indicate that GH or a peptide related to GH may be involved in the regulation of hepatic PRL receptors. However, the results do not rule out the possibility that rPRL, when present in doses other than those used in the present investigation, may also play a role in receptor regulation.
Hypophysectomy
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ABSTRACT The administration of thyrotrophin-releasing hormone (TRH) causes a variety of dopamine-related biological events. To understand the specific role of TRH on rat hypothalamic dopamine neurones, we examined the in-vivo effects of intraventricular (i.c.v.) infusion of TRH on the release and synthesis of prolactin in the rat pituitary gland and on the changes in binding of [ 3 H]MeTRH and dopamine turnover rates in rat hypothalamus. We have also examined the in-vitro effects of TRH on the release of [ 3 H]dopamine from dispersed tuberoinfundibular dopamine neurones. Female rats were treated with i.c.v. infusions of 1 μmol TRH/l daily for 1, 3 and 7 days using Alzet osmotic pumps. Following 7 days of treatment the serum prolactin concentrations were significantly decreased. A reduction in hypothalamic TRH-binding sites (B max ) was also apparent but the dissociation constant ( K d ) was unaffected. Northern blot analysis of total RNA isolated from the pituitary glands of control animals using 32 P-labelled prolactin cDNA as a probe indicated the presence of three species of prolactin gene transcripts of approximately 3·7, 2·0 and 1·0 kb in size, and these were decreased by TRH treatment. We examined the turnover rate of dopamine in the rat hypothalamus when TRH was administered i.c.v. for 7 days. There was a significant increase in 3,4-dihydroxyphenylacetic acid/dopamine ratio with TRH treatment. Moreover, exposure to TRH stimulated [ 3 H]dopamine release from rat tuberoinfundibular neurones in a time- and dose-dependent manner. Dopamine receptor antagonists such as SCH23390 and (−)sulpiride, and other neuropeptides such as vasoactive intestinal peptide and oxytocin did not affect TRH-stimulated [ 3 H]dopamine release. These data suggest that i.c.v. administration of TRH might decrease both prolactin secretion and accumulation of prolactin gene transcripts in the pituitary by stimulating dopamine release from tuberoinfundibular neurones. Journal of Endocrinology (1992) 133, 59–66
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In order to study whether changes in adenohypophysial dopamine are only related to PRL release or also to the variation of LH or FSH, dopamine (DA) in the pars distalis was measured during the estrous cycle and after castration of both male and female rats. Catecholamines were assayed using a highly sensitive radioenzymatic method. Dopamine and norepinephrine were also measured in the median eminence of the same rats. Adenohypophysial dopamine fluctuates during the estrous cycle, reaching its lowest levels on the afternoon of proestrus. Ovariectomy increases the DA content of the anterior lobe and estrogens reverse this effect. Orchidectomy does not change the amount of DA in the anterior pituitary. DA concentration in the median eminence parallels the changes observed in the pars distalis. We conclude that anterior pituitary dopamine concentration is closely related to PRL release and is not associated with changes in the release of LH or FSH.
Median eminence
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The changes in adenohypophysial and hypothalamic content and in hypothalamic release of dopamine and thyrotrophin-releasing hormone (TRH) into the hypophysial portal system during the suckling-induced release of prolactin were investigated. An increase in peripheral plasma levels of prolactin was induced by mammary nerve stimulation in urethane-anaesthetized and by suckling in unanaesthetized lactating rats. In the unanaesthetized rat, suckling caused a decrease of dopamine levels in hypothalamus and adenohypophysis and a short-lasting small increase in hypothalamic TRH. Mammary nerve stimulation induced a transient decrease in dopamine levels and an increase in TRH levels in hypophysial stalk blood. To assess the significance of the observed changes in dopamine and TRH levels for prolactin release, these changes in dopamine and TRH were mimicked in lactating rats anaesthetized with urethane and pretreated with α-methyl-p-tyrosine (AM p T, a competitive inhibitor of catecholamine synthesis). Reducing hypothalamic dopamine secretion by treatment with AM p T increased peripheral plasma levels of prolactin from 15 to 477 ng/ml; an infusion with dopamine, resulting in plasma levels similar to those measured in hypophysial stalk plasma, reduced plasma levels of prolactin to 127 ng/ml. Neither a 50% reduction in dopamine infusion rate for 15 min nor administration of 100 ng TRH caused an appreciable change in plasma prolactin levels. However, when dopamine infusion was reduced by 50% for 15 min just before TRH was injected, then an increase in plasma levels of prolactin from 172 to 492 ng/ml was observed. Thus, the effectiveness of TRH in releasing prolactin in the lactating rat was enhanced when a transient decrease of dopamine levels occurred before treatment with TRH. It is concluded that the changes observed in dopamine and TRH levels in hypophysial stalk blood are involved in the suckling-induced prolactin release in an important manner.
Prolactin cell
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Pancreatic Islets
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Corticosterone
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The effects of dopamine on PRL secretion and lysosomal enzyme activity in anterior pituitary tissue from rats selected during various stages of the estrous cycle were examined under in vitro conditions. During the estrous cycle, there was a marked variation in the capacity of dopamine to stimulate the activity of the lysosomal enzyme β-glucuronidase in the anterior pituitary gland. Moreover, this variation in the responsiveness of pituitary tissue to the stimulatory action of dopamine on β-glucuronidase activity was accompanied by a similar variation in the responsiveness of the tissue to the inhibitory action of dopamine on PRL release. Anterior pituitary glands from diestrous rats were the most sensitive to the actions of dopamine on β-glucuronidase activity and PRL release, whereas glands from estrous animals were the least sensitive. Ovariectomy on the day of diestrus prevented the decline in the responsiveness of the anterior lobe to the actions of dopamine normally seen 2 days later (on the presumptive day of estrus). On the other hand, when animals were treated with estradiol benzoate during the 2 days after ovariectomy, the responsiveness of the pituitary tissue to dopamine was markedly suppressed and was similar to that of tissue from estrous rats. When rats were treated with progesterone during the 2 days after ovariectomy, the responsiveness of the anterior lobe to dopamine was similar to that in ovariectomized controls. It is suggested that the decrease in the responsiveness of the anterior pituitary gland to the actions of dopamine on lysosomal enzyme activity and PRL release that occurs between diestrus and estrus is estrogen mediated. It is also suggested that the ability of estrogen to antagonize the inhibitory effect of dopamine on PRL release may be mediated through an estrogen-induced reduction in the capacity of dopamine to stimulate lysosomal enzyme activity in the anterior pituitary gland. (Endocrinology108: 903, 1981)
Prolactin cell
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Genetically obese hyperglycemic mice (ob/ob) were compared with their nonlittermate lean controls at 4–5 months of age with regard to brain serotonin, pituitary ACTH content, and circulating levels of glucose, glucagon, insulin, TSH, T3, T4, total tryptophan, and free tryptophan. Brain serotonin, pituitary ACTH content, and plasma insulin, glucose, total tryptophan, and free tryptophan were all significantly higher in obeSe mice than in the controls. TSH, T3, and T4 were not significantly different in obese mice vs. controls, suggesting that the obese mouse is euthyroid. Fasting improved but failed to normalize the glucose and insulin levels or insulin to glucagon ratios. Since serotonin is an important neurotransmitter with regard to hypothalamic-pituitary function and since its levels in the brain are dependent on the availability of tryptophan, the findings of elevated levels of free tryptophan in the plasma and serotonin in the brain of the obese hyperglycemic mouse may help to explain some of the previously observed abnormalities of pituitary hormone secretion in these animals.
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