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Lydia A Arbogast - One of the best experts on this subject based on the ideXlab platform.
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mu and kappa opioid receptor expression in the mediobasal hypothalamus and effectiveness of selective antagonists on Prolactin Release during lactation
Neuroscience, 2010Co-Authors: Mahboubeh Tavakolinezhad, Lydia A ArbogastAbstract:Abstract Endogenous opioid peptides are involved in Prolactin Release during lactation, in part by decreasing tuberoinfundibular dopaminergic (TIDA) neuronal activity. Both mu (μ) and kappa (κ) opioid receptors have a role in the suckling-induced Prolactin rise after 4–5 h up deprivation. The aim of this study was to investigate effects of μ opioid receptor antagonist, β-funaltrexamine (β-FNA), and κ opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on Prolactin secretion and TIDA neuronal activity in lactating rats after 18 h pup deprivation. After 4 h separation from pups, the suckling-induced Prolactin rise was abolished by 16 μg nor-BNI and 5 μg β-FNA, coincident with increased dihydroxyphenylacetic acid (DOPAC):dopamine ratio in the stalk-median eminence (SME). However, after 18 h pups separation, these same doses of nor-BNI and β-FNA did not alter the Prolactin surge or DOPAC:dopamine ratios in the SME. Higher doses of nor-BNI (32 μg) and β-FNA (10 μg) were required to inhibit suckling-induced Prolactin secretion. β-FNA (10 μg) increased the DOPAC:dopamine ratio in the SME, whereas nor-BNI (32 μg) treatment had no effect. The μ and κ opioid receptor mRNA levels in the mediobasal hypothalamus were similar to suckled control rats after 4 h pup deprivation, but increased 1.4-fold after 18 h pup deprivation. These data support involvement of endogenous opioidergic systems in the suckling-induced Prolactin rise after a prolonged (18 h) period of pup deprivation, as well as the shorter (4 h) pup deprivation period previously reported. Suppression of TIDA neuronal activity likely played a part in μ opioid receptor input to the suckling-induced Prolactin rise after both 4 h and 18 h separation, whereas non-dopaminergic input was implicated with κ opioid receptors after 18 h pup deprivation. Increased μ and κ opioid receptors gene expression in the mediobasal hypothalamus may contribute to reduced effectiveness of opioid receptor antagonists to block suckling-induced Prolactin Release after 18 h pup deprivation.
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mu and kappa opioid receptor expression in the mediobasal hypothalamus and effectiveness of selective antagonists on Prolactin Release during lactation
Neuroscience, 2010Co-Authors: Mahboubeh Tavakolinezhad, Lydia A ArbogastAbstract:Endogenous opioid peptides are involved in Prolactin Release during lactation, in part by decreasing tuberoinfundibular dopaminergic (TIDA) neuronal activity. Both mu (mu) and kappa (kappa) opioid receptors have a role in the suckling-induced Prolactin rise after 4-5 h up deprivation. The aim of this study was to investigate effects of mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), and kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on Prolactin secretion and TIDA neuronal activity in lactating rats after 18 h pup deprivation. After 4 h separation from pups, the suckling-induced Prolactin rise was abolished by 16 microg nor-BNI and 5 microg beta-FNA, coincident with increased dihydroxyphenylacetic acid (DOPAC):dopamine ratio in the stalk-median eminence (SME). However, after 18 h pups separation, these same doses of nor-BNI and beta-FNA did not alter the Prolactin surge or DOPAC:dopamine ratios in the SME. Higher doses of nor-BNI (32 microg) and beta-FNA (10 microg) were required to inhibit suckling-induced Prolactin secretion. beta-FNA (10 microg) increased the DOPAC:dopamine ratio in the SME, whereas nor-BNI (32 microg) treatment had no effect. The mu and kappa opioid receptor mRNA levels in the mediobasal hypothalamus were similar to suckled control rats after 4 h pup deprivation, but increased 1.4-fold after 18 h pup deprivation. These data support involvement of endogenous opioidergic systems in the suckling-induced Prolactin rise after a prolonged (18 h) period of pup deprivation, as well as the shorter (4 h) pup deprivation period previously reported. Suppression of TIDA neuronal activity likely played a part in mu opioid receptor input to the suckling-induced Prolactin rise after both 4 h and 18 h separation, whereas non-dopaminergic input was implicated with kappa opioid receptors after 18 h pup deprivation. Increased mu and kappa opioid receptors gene expression in the mediobasal hypothalamus may contribute to reduced effectiveness of opioid receptor antagonists to block suckling-induced Prolactin Release after 18 h pup deprivation.
Charles G D Brook - One of the best experts on this subject based on the ideXlab platform.
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hexarelin induced growth hormone cortisol and Prolactin Release a dose response study
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Ahmed F Massoud, Peter C. Hindmarsh, Charles G D BrookAbstract:Dose-response data for GH-releasing peptides are limited. We studied the effects of varying doses (0-1.0 microgram/kg) of hexarelin, a novel GH-releasing peptide, administered iv to healthy adult males on GH, PRL, and cortisol Release. In addition, we studied the effect of administration of a single dose of GHRH-(1-29)-NH2 (1.0 microgram/kg), alone or in combination with a low dose of hexarelin (0.125 microgram/kg). Dose-response curves for the maximum GH response and maximum percent change in serum PRL and cortisol concentrations from baseline were constructed. The GH dose-response curve reached a plateau of 140 mU/L, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.48 +/- 0.02 microgram/kg (mean +/- SEM). The PRL dose-response curve reached a plateau of 180% for the maximum percent rise from baseline, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.39 +/- 0.02 microgram/kg. The cortisol dose-response curve showed a step increase to approximately 40% at a ...
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hexarelin induced growth hormone cortisol and Prolactin Release a dose response study
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Ahmed F Massoud, Peter C. Hindmarsh, Charles G D BrookAbstract:Dose-response data for GH-releasing peptides are limited. We studied the effects of varying doses (0-1.0 microgram/kg) of hexarelin, a novel GH-releasing peptide, administered iv to healthy adult males on GH, PRL, and cortisol Release. In addition, we studied the effect of administration of a single dose of GHRH-(1-29)-NH2 (1.0 microgram/kg), alone or in combination with a low dose of hexarelin (0.125 microgram/kg). Dose-response curves for the maximum GH response and maximum percent change in serum PRL and cortisol concentrations from baseline were constructed. The GH dose-response curve reached a plateau of 140 mU/L, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.48 +/- 0.02 microgram/kg (mean +/- SEM). The PRL dose-response curve reached a plateau of 180% for the maximum percent rise from baseline, corresponding to a hexarelin dose of 1.0 microgram/kg, with an ED50 of 0.39 +/- 0.02 microgram/kg. The cortisol dose-response curve showed a step increase to approximately 40% at a ...
Cheryl S Watson - One of the best experts on this subject based on the ideXlab platform.
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signaling from the membrane via membrane estrogen receptor α estrogens xenoestrogens and phytoestrogens
Steroids, 2005Co-Authors: Cheryl S Watson, Nataliya N Bulayeva, Ann L Wozniak, Celeste C FinnertyAbstract:Abstract Estrogen mimetics in the environment and in foods can have important consequences for endocrine functions. When previously examined for action via genomic steroid signaling mechanisms, most of these compounds were found to be very weak agonists. We have instead tested their actions via several membrane-initiated signaling mechanisms in GH3/B6 pituitary tumor cells extensively selected for high (responsive) or low (nonresponsive) expression of the membrane version of estrogen receptor-α (mERα). We found many estrogen mimetic compounds to be potently active in our quantitative extracellular-regulated kinase (ERK) activation assays, to increase cellular Ca++ levels, and to cause rapid Prolactin Release. However, these compounds may activate one or both mechanisms with different potencies. For instance, some compounds activate ERKs in both pM and nM concentration ranges, while others are only active at nM and higher concentrations. Compounds also show great differences in their temporal activation patterns. While estradiol causes a bimodal time-dependent ERK activation (peaking at both 3 and 30 min), most estrogen mimetics cause either an early phase activation, a late phase activation, or an early sustained activation. One xenoestrogen known to be a relatively potent activator of estrogen response element-mediated actions (bisphenol A) is inactive as an ERK activator, and only a modest inducer of Ca++ levels and Prolactin Release. Many different signaling machineries culminate in ERK activation, and xenoestrogens differentially affect various pathways. Clearly individual xenoestrogens must be individually investigated for their differing abilities to activate distinct membrane-initiated signal cascades that lead to a variety of cellular functions.
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signaling from the membrane via membrane estrogen receptor α estrogens xenoestrogens and phytoestrogens
Steroids, 2005Co-Authors: Cheryl S Watson, Nataliya N Bulayeva, Ann L Wozniak, Celeste C FinnertyAbstract:Abstract Estrogen mimetics in the environment and in foods can have important consequences for endocrine functions. When previously examined for action via genomic steroid signaling mechanisms, most of these compounds were found to be very weak agonists. We have instead tested their actions via several membrane-initiated signaling mechanisms in GH3/B6 pituitary tumor cells extensively selected for high (responsive) or low (nonresponsive) expression of the membrane version of estrogen receptor-α (mERα). We found many estrogen mimetic compounds to be potently active in our quantitative extracellular-regulated kinase (ERK) activation assays, to increase cellular Ca++ levels, and to cause rapid Prolactin Release. However, these compounds may activate one or both mechanisms with different potencies. For instance, some compounds activate ERKs in both pM and nM concentration ranges, while others are only active at nM and higher concentrations. Compounds also show great differences in their temporal activation patterns. While estradiol causes a bimodal time-dependent ERK activation (peaking at both 3 and 30 min), most estrogen mimetics cause either an early phase activation, a late phase activation, or an early sustained activation. One xenoestrogen known to be a relatively potent activator of estrogen response element-mediated actions (bisphenol A) is inactive as an ERK activator, and only a modest inducer of Ca++ levels and Prolactin Release. Many different signaling machineries culminate in ERK activation, and xenoestrogens differentially affect various pathways. Clearly individual xenoestrogens must be individually investigated for their differing abilities to activate distinct membrane-initiated signal cascades that lead to a variety of cellular functions.
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rapid actions of estrogens in gh3 b6 pituitary tumor cells via a plasma membrane version of estrogen receptor α
Steroids, 1999Co-Authors: Cheryl S Watson, Andrea M Norfleet, Todd C Pappas, Bahiru GametchuAbstract:The focus of our work on rapid actions of estrogens has been on the immuno-identification of a membrane version of the estrogen receptor-α (mERα) and the correlation of the presence of this receptor to the rapid secretion of Prolactin in pituitary tumor cells. We demonstrated the mERα by both fluorescence and immuno-enzyme-cytochemistry and with both conventional and confocal microscopy in the cell line GH3/B6 and its sublines. Its presence on cells (including recently subcloned ones) is very heterogenous, unlike the nuclear ERα, which is present in every cell. An impeded ligand (estradiol covalently linked to BSA) binds to mERα and elicits the same response. A total of eight antibodies to ERα recognize mERα, making it likely that the membrane and nuclear proteins are highly related. Immuno-identification techniques have also been used to identify mERα on the MCF-7 human breast cancer cell line. Estradiol at very low concentrations elicits Prolactin Release from GH3/B6 cells within a few minutes of application. This response is bimodal, with effective concentrations in both the picomolar and nanomolar ranges. Prolactin Release is also elicited or inhibited by ERα-specific antibodies. The characteristics of mERα and the membrane receptor for glucocorticoids have many similarities, suggesting that this mode of subcellular location/function alternative might be used by other members of the gene family.
Johannes H. Proost - One of the best experts on this subject based on the ideXlab platform.
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modeling of Prolactin response following dopamine d2 receptor antagonists in rats can it be translated to clinical dosing
Pharmacology Research & Perspectives, 2017Co-Authors: A. Taneja, An Vermeulen, Dymphy Huntjens, Meindert Danhof, Elizabeth C. M. Lange, Johannes H. ProostAbstract:Prolactin Release is a side effect of antipsychotic therapy with dopamine antagonists, observed in rats as well as humans. We examined whether two semimechanistic models could describe Prolactin response in rats and subsequently be translated to predict pituitary dopamine D2 receptor occupancy and plasma Prolactin concentrations in humans following administration of paliperidone or remoxipride. Data on male Wistar rats receiving single or multiple doses of risperidone, paliperidone, or remoxipride was described by two semimechanistic models, the precursor pool model and the agonist-antagonist interaction model. Using interspecies scaling approaches, human D2 receptor occupancy and plasma Prolactin concentrations were predicted for a range of clinical paliperidone and remoxipride doses. The predictions were compared with corresponding observations described in literature as well as with predictions from published models developed on human data. The pool model could predict D2 receptor occupancy and Prolactin response in humans following single doses of paliperidone and remoxipride. Tolerance of Prolactin Release was predicted following multiple doses. The interaction model underpredicted both D2 receptor occupancy and Prolactin response. Prolactin elevation may be deployed as a suitable biomarker for interspecies translation and can inform the clinical safe and effective dose range of antipsychotic drugs. While the pool model was more predictive than the interaction model, it overpredicted tolerance on multiple dosing. Shortcomings of the translations reflect the need for better mechanistic models.
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a comparison of two semi mechanistic models for Prolactin Release and prediction of receptor occupancy following administration of dopamine d2 receptor antagonists in rats
European Journal of Pharmacology, 2016Co-Authors: A. Taneja, An Vermeulen, Dymphy Huntjens, Elizabeth C. M. Lange, Johannes H. ProostAbstract:We compared the model performance of two semi-mechanistic pharmacokinetic-pharmacodynamic models, the precursor pool model and the agonist-antagonist interaction model, to describe Prolactin response following the administration of the dopamine D2 receptor antagonists risperidone, paliperidone or remoxipride in rats. The time course of pituitary dopamine D2 receptor occupancy was also predicted. Male Wistar rats received a single dose (risperidone, paliperidone, remoxipride) or two consecutive doses (remoxipride). Population modeling was applied to fit the pool and interaction models to the Prolactin data. The pool model was modified to predict the time course of pituitary D2 receptor occupancy. Unbound plasma concentrations of the D2 receptor antagonists were considered the drivers of the Prolactin response. Both models were used to predict Prolactin Release following multiple doses of paliperidone. Both models described the data well and model performance was comparable. Estimated unbound EC50 for risperidone and paliperidone was 35.1nM (relative standard error 51%) and for remoxipride it was 94.8nM (31%). KI values for these compounds were 11.1nM (21%) and 113nM (27%), respectively. Estimated pituitary D2 receptor occupancies for risperidone and remoxipride were comparable to literature findings. The interaction model better predicted Prolactin profiles following multiple paliperidone doses, while the pool model predicted tolerance better. The performance of both models in describing the Prolactin profiles was comparable. The pool model could additionally describe the time course of pituitary D2 receptor occupancy. Prolactin response following multiple paliperidone doses was better predicted by the interaction model.
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summary data of potency and parameter information from semi mechanistic pkpd modeling of Prolactin Release following administration of the dopamine d2 receptor antagonists risperidone paliperidone and remoxipride in rats
Data in Brief, 2016Co-Authors: A. Taneja, An Vermeulen, Dymphy Huntjens, Meindert Danhof, Elizabeth C. M. Lange, Johannes H. ProostAbstract:We provide the reader with relevant data related to our recently published paper, comparing two mathematical models to describe Prolactin turnover in rats following one or two doses of the dopamine D2 receptor antagonists risperidone, paliperidone and remoxipride, "A comparison of two semi-mechanistic models for Prolactin Release and prediction of receptor occupancy following administration of dopamine D2 receptor antagonists in rats" (Taneja et al., 2016) [1]. All information is tabulated. Summary level data on the in vitro potencies and the physicochemical properties is presented in Table 1. Model parameters required to explore the precursor pool model are presented in Table 2. In Table 3, estimated parameter comparisons for both models are presented, when separate potencies are estimated for risperidone and paliperidone, as compared to a common potency for both drugs. In Table 4, parameter estimates are compared when the drug effect is parameterized in terms of drug concentration or receptor occupancy.
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Translational modelling of Prolactin response following administration of D2 antagonists in rats
2015Co-Authors: A. Taneja, An Vermeulen, Dymphy Huntjens, Meindert Danhof, Ecm De Lange, Johannes H. ProostAbstract:Objectives: Treatment with D2 antagonists results in Prolactin Release, and thus Prolactin is a biomarker of dopamine antagonism. We compare the model performance of two semi-mechanistic PKPD models, the pool model and the agonist-antagonist interaction model, to describe Prolactin Release following administration of risperidone (RI), paliperidone (PA) or remoxipride (REM) in rats. The hypothesis that potency differences exist for risperidone and paliperidone was evaluated and rat to human translations were conducted. Methods: The models were fitted to single or multiple dose data on the 3 paradigm compounds. Different potencies (EC50 and KI) were estimated for RI and PA, as compared to a common potency. The pool model was modified to estimate RO50, or the receptor occupancy at half-maximal effect, a system specific parameter. This was done using model predicted and observed KI values. As peripheral D2 antagonism is responsible for Prolactin Release, free population plasma concentrations of the D2 antagonists were considered as the drivers of the pharmacodynamic (PD) response. Finally, we predicted the time course of plasma Prolactin in humans following PA administration, using an inter-species scaling approach. Results: Both models were able to describe the data and model performance was comparable. Potencies of RI and PA did not differ significantly. Estimated EC50 for RI and PA was 35.1(relative standard error 51%) and for REM it was 94.8 (31%) nM. KI values for these compounds were 14.6 (17%) and 165 (14%) nM respectively. RO50 was 28.7 (21%) %. System specific PD parameters were scaled using allometric principles, while RO50 was assumed to be species independent. Predicted human plasma Prolactin profiles were comparable with observed and published findings. Tachyphylaxis due to depletion of the Prolactin pool was predicted after the second dose. Conclusions: The performance of both models was comparable in describing single and multiple dose data. Single dose typical human predictions with the pool model were in agreement with observed data.
Mahboubeh Tavakolinezhad - One of the best experts on this subject based on the ideXlab platform.
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mu and kappa opioid receptor expression in the mediobasal hypothalamus and effectiveness of selective antagonists on Prolactin Release during lactation
Neuroscience, 2010Co-Authors: Mahboubeh Tavakolinezhad, Lydia A ArbogastAbstract:Abstract Endogenous opioid peptides are involved in Prolactin Release during lactation, in part by decreasing tuberoinfundibular dopaminergic (TIDA) neuronal activity. Both mu (μ) and kappa (κ) opioid receptors have a role in the suckling-induced Prolactin rise after 4–5 h up deprivation. The aim of this study was to investigate effects of μ opioid receptor antagonist, β-funaltrexamine (β-FNA), and κ opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on Prolactin secretion and TIDA neuronal activity in lactating rats after 18 h pup deprivation. After 4 h separation from pups, the suckling-induced Prolactin rise was abolished by 16 μg nor-BNI and 5 μg β-FNA, coincident with increased dihydroxyphenylacetic acid (DOPAC):dopamine ratio in the stalk-median eminence (SME). However, after 18 h pups separation, these same doses of nor-BNI and β-FNA did not alter the Prolactin surge or DOPAC:dopamine ratios in the SME. Higher doses of nor-BNI (32 μg) and β-FNA (10 μg) were required to inhibit suckling-induced Prolactin secretion. β-FNA (10 μg) increased the DOPAC:dopamine ratio in the SME, whereas nor-BNI (32 μg) treatment had no effect. The μ and κ opioid receptor mRNA levels in the mediobasal hypothalamus were similar to suckled control rats after 4 h pup deprivation, but increased 1.4-fold after 18 h pup deprivation. These data support involvement of endogenous opioidergic systems in the suckling-induced Prolactin rise after a prolonged (18 h) period of pup deprivation, as well as the shorter (4 h) pup deprivation period previously reported. Suppression of TIDA neuronal activity likely played a part in μ opioid receptor input to the suckling-induced Prolactin rise after both 4 h and 18 h separation, whereas non-dopaminergic input was implicated with κ opioid receptors after 18 h pup deprivation. Increased μ and κ opioid receptors gene expression in the mediobasal hypothalamus may contribute to reduced effectiveness of opioid receptor antagonists to block suckling-induced Prolactin Release after 18 h pup deprivation.
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mu and kappa opioid receptor expression in the mediobasal hypothalamus and effectiveness of selective antagonists on Prolactin Release during lactation
Neuroscience, 2010Co-Authors: Mahboubeh Tavakolinezhad, Lydia A ArbogastAbstract:Endogenous opioid peptides are involved in Prolactin Release during lactation, in part by decreasing tuberoinfundibular dopaminergic (TIDA) neuronal activity. Both mu (mu) and kappa (kappa) opioid receptors have a role in the suckling-induced Prolactin rise after 4-5 h up deprivation. The aim of this study was to investigate effects of mu opioid receptor antagonist, beta-funaltrexamine (beta-FNA), and kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on Prolactin secretion and TIDA neuronal activity in lactating rats after 18 h pup deprivation. After 4 h separation from pups, the suckling-induced Prolactin rise was abolished by 16 microg nor-BNI and 5 microg beta-FNA, coincident with increased dihydroxyphenylacetic acid (DOPAC):dopamine ratio in the stalk-median eminence (SME). However, after 18 h pups separation, these same doses of nor-BNI and beta-FNA did not alter the Prolactin surge or DOPAC:dopamine ratios in the SME. Higher doses of nor-BNI (32 microg) and beta-FNA (10 microg) were required to inhibit suckling-induced Prolactin secretion. beta-FNA (10 microg) increased the DOPAC:dopamine ratio in the SME, whereas nor-BNI (32 microg) treatment had no effect. The mu and kappa opioid receptor mRNA levels in the mediobasal hypothalamus were similar to suckled control rats after 4 h pup deprivation, but increased 1.4-fold after 18 h pup deprivation. These data support involvement of endogenous opioidergic systems in the suckling-induced Prolactin rise after a prolonged (18 h) period of pup deprivation, as well as the shorter (4 h) pup deprivation period previously reported. Suppression of TIDA neuronal activity likely played a part in mu opioid receptor input to the suckling-induced Prolactin rise after both 4 h and 18 h separation, whereas non-dopaminergic input was implicated with kappa opioid receptors after 18 h pup deprivation. Increased mu and kappa opioid receptors gene expression in the mediobasal hypothalamus may contribute to reduced effectiveness of opioid receptor antagonists to block suckling-induced Prolactin Release after 18 h pup deprivation.
