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Rita J. Valentino - One of the best experts on this subject based on the ideXlab platform.
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increased vulnerability of the brain norepinephrine system of females to corticotropin Releasing Factor overexpression
Molecular Psychiatry, 2013Co-Authors: Debra A Bangasser, E.j. Van Bockstaele, B A S Reyes, David A Piel, V Garachh, Xy Zhang, Zach Plona, Sheryl G Beck, Rita J. ValentinoAbstract:Increased vulnerability of the brain norepinephrine system of females to corticotropin-Releasing Factor overexpression
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Previous stress alters corticotropin-Releasing Factor neurotransmission in the locus coeruleus
Neuroscience, 1995Co-Authors: Andre L. Curtis, Luis A. Pavcovich, Dimitri E. Grigoriadis, Rita J. ValentinoAbstract:Abstract Spontaneous and stress-evoked discharge of locus coeruleus neurons were characterized in rats with a history of stress. Rats exposed to one or five daily 30-min sessions of footshock were anesthetized with halothane and surgically prepared for locus coeruleus single-unit recording immediately following the last session. Locus coeruleus spontaneous discharge rate and discharge evoked by sciatic nerve stimulation were comparable between acutely and repeatedly stressed rats and controls. In contrast, locus coeruleus activation produced by intracerebroventricular administration of corticotropin-Releasing Factor (3 μg) or by hypotensive challenge (which requires endogenous corticotropin-Releasing Factor release in the locus coeruleus) was greatly attenuated in acutely stressed rats. The corticotropin-Releasing Factor dose-response curve was shifted to the right in acutely stressed rats compared with controls. In repeatedly stressed rats, the effects of 3 μg corticotropin-Releasing Factor on locus coeruleus discharge were similarly diminished. Although the maximum effect produced by corticotropin-Releasing Factor was decreased in these rats, the dose-response curve was shifted to the left, indicative of sensitization. Hypotensive challenge, which was ineffective in acutely stressed rats, increased locus coeruleus discharge of repeatedly stressed rats by a similar magnitude as in matched controls. The return of locus coeruleus responsiveness to hypotension in repeatedly stressed rats may be related to the sensitization to corticotropin-Releasing Factor. Finally, the protocol of repeated stress did not alter the affinity or density of corticotropin-Releasing Factor receptors in either the frontal cortex or brainstem. Taken together, the results suggest that a history of stress alters corticotropin-Releasing Factor neurotransmission in the locus coeruleus at the postsynaptic level. However, these effects are not reflected by corticotropin-Releasing Factor binding kinetics in brainstem. Stress-induced changes in corticotropin-Releasing Factor neurotransmitter function in the locus coeruleus may play a role in certain symptoms of stress-related psychiatric disorders.
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Corticotropin-Releasing Factor innervation of the locus coeruleus region: distribution of fibers and sources of input.
Neuroscience, 1992Co-Authors: Rita J. Valentino, Michelle E. Page, E.j. Van Bockstaele, Gary Aston-jonesAbstract:Electrophysiologic studies support the hypothesis that corticotropin-Releasing Factor, the neurohormone that initiates adrenocorticotropin release during stress, also serves as a neurotransmitter in the pontine noradrenergic nucleus, the locus coeruleus. To elucidate the circuitry underlying proposed corticotropin-Releasing Factor neurotransmission in the locus coeruleus, the present study utilized immunohistochemical techniques to characterize corticotropin-Releasing Factor innervation of rat locus coeruleus and pericoerulear regions. Corticotropin-Releasing Factor-like immunoreactive fibers were identified in the locus coeruleus of colchicine- and non-colchicine-treated rats. However, corticotropin-Releasing Factor innervation of pericoerulear regions rostral and lateral to the locus coeruleus was more dense than that of the locus coeruleus proper. Double-labeling studies utilizing antisera directed against corticotropin-Releasing Factor and tyrosine hydroxylase indicated that corticotropin-Releasing Factor-like immunoreactive fibers overlap with tyrosine hydroxylase-like immunoreactive processes of locus coeruleus neurons, particularly in rostral medial and lateral regions. A group of corticotropin-Releasing Factor-like immunoreactive neurons was localized just lateral to the locus coeruleus and numerous corticotropin-Releasing Factor-like immunoreactive neurons were visualized just ventral to the rostral pole of the locus coeruleus in a region corresponding to Barrington's nucleus. None of these corticotropin-Releasing Factor-like immunoreactive neurons were tyrosine hydroxylase-positive. To determine the source of corticotropin-Releasing Factor-like immunoreactive fibers in the locus coeruleus, injections of the retrograde tracer [wheat germ agglutinin conjugated to inactivated (apo) horseradish peroxidase coupled to gold particles] were made into the locus coeruleus and sections were processed for corticotropin-Releasing Factor-like immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Ha Tucker - One of the best experts on this subject based on the ideXlab platform.
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Comparison of growth hormone-Releasing Factor and somatotropin: thyroid status of lactating, primiparous cows.
Journal of dairy science, 1995Co-Authors: S Kahl, Anthony V. Capuco, Mario Binelli, Wk Vanderkooi, Ha Tucker, MoseleyAbstract:Effects of recombinant bovine growth hormone-Releasing Factor and recombinant bST on thyroxine 5'-deiodinase activities of liver and mammary gland were studied for lactating cows. Beginning on d 118 of lactation, 30 primiparous Holsteins received continuous infusions of 12 mg/d of Releasing Factor or 29 mg/d of bST or served as uninfused controls for 63 d. Blood samples were collected on d 1, 29, and 57, and samples of whole milk were collected at the early afternoon milking on d -5, 30, and 58. Liver and mammary tissue samples were obtained at slaughter on d 63. Infusion of Releasing Factor and bST decreased serum concentration of triiodothyronine by 10% and the ratio of triiodothyronine to thyroxine in serum by 20%. Concentrations of circulating triiodothyronine reflected a 30% decrease in hepatic 5'-deiodinase activity in response to infusion with Releasing Factor and bST. In contrast, treatment with Releasing Factor and bST did not affect 5'-deiodinase activity in the mammary gland and did not alter triiodothyronine concentration in milk. Data suggest that Releasing Factor and bST increase the hypothyroid status of the lactating cow and maintain an euthyroid condition in the mammary gland, thus enhancing the metabolic priority of the mammary gland.
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Comparison of growth hormone-Releasing Factor and somatotropin: body growth and lactation of primiparous cows
Journal of dairy science, 1995Co-Authors: Mario Binelli, Wk Vanderkooi, L.t. Chapin, W.m. Moseley, Michael J. Vandehaar, J.d. Turner, Ha TuckerAbstract:Growth hormone-Releasing Factor is the main endogenous stimulator of somatotropin secretion. Our objective was to compare the effects of recombinant growth hormone-Releasing Factor and recombinant bST on somatotropin secretion, mammary function, and body composition of lactating, primiparous dairy cows. Cows (118 d of lactation) served as uninfused controls or were infused for 63 d with 12 mg/d of Releasing Factor or with 29 mg/d of bST. These doses elevated somatotropin in serum to concentrations of similar magnitude. The Releasing Factor and bST each similarly increased milk yield, yield of milk components, weight of most organs, mobilization of adipose tissue, accretion of lean tissue in the carcass, and metabolic activity (RNA) of mammary tissue. Relative to controls, neither Releasing Factor nor bST significantly affected cell numbers (DNA) in mammary glands or concentrations of plasmin in milk. None of the variables measured provided evidence for galactopoietic effects of Releasing Factor independent of somatotropin.
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Galactopoietic Effects of a (1-30)NH2 Analog of Growth Hormone-Releasing Factor in Dairy Cows
Journal of dairy science, 1994Co-Authors: Geoffrey E. Dahl, L.t. Chapin, W.m. Moseley, M. B. Kamdar, Ha TuckerAbstract:Two experiments were conducted to determine the galactopoietic effects of an analog of growth hormone-Releasing Factor. Specific replacements were made in the AA sequence of growth hormone-Releasing Factor to produce a growth hormone-Releasing Factor analog with enhanced stability in vivo. In Experiment 1, 24 Holstein cows were infused i.v. with 0, .33, 1, or 3 mg/d of growth hormone-Releasing Factor analog for 20 d. Infusion of the analog increased mean serum concentrations of somatotropin, IGF-I, and NEFA. The analog also increased milk yield as much as 44% relative to that of controls. In Experiment 2, 24 Holstein cows were infused i.v. with 0, .11, .33, or 1 mg/d of analog for 60 d. Infusion of analog increased serum concentrations of somatotropin, IGF-I, and NEFA in a dose-dependent manner. At 1 mg/d, the analog increased SCM yield 28% throughout the infusion period relative to the 0 mg/d controls. In summary, a growth hormone-Releasing Factor analog increased milk yield and serum concentrations of somatotropin and IGF-I. Furthermore, this galactopoietic activity was mediated through the somatotropic axis.
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Galactopoietic effects of recombinant somatotropin and growth hormone-Releasing Factor in dairy cows.
Journal of dairy science, 1993Co-Authors: Geoffrey E. Dahl, L.t. Chapin, W.m. Moseley, Ha TuckerAbstract:Abstract Eight Holsteins per group received 12 mg/d of recombinant growth hormone-Releasing Factor or 29 mg/d of recombinant bST or served as untreated controls for 60 d. Milk yield and composition were measured for 10 d before infusion, during infusion (d 0 to 59), and for 20 d after infusion ended. Compared with controls, bST and growth hormone-Releasing Factor increased SCM during infusion. The SCM yield of cows treated with growth hormone-Releasing Factor was greater than that of bST-treated cows during the final 20 d of infusion. Relative to controls, bST and growth hormone-Releasing Factor increased serum concentrations of somatotropin and IGF-I during infusion. Concentrations of somatotropin and IGF-I in serum of bST-and growth hormone-Releasing Factor-treated cows did not differ during infusion. In summary, growth hormone-Releasing Factor increased SCM yield more than bST, despite similar serum concentrations of somatotropin and IGF-I. Thus, the galactopoietic action of growth hormone-Releasing Factor was not explained solely by elevation of total radioimmunoassayable somatotropin and IGF-I in serum.
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Comparison of somatotropin and growth hormone-Releasing Factor on milk yield, serum hormones, and energy status.
Journal of dairy science, 1991Co-Authors: Geoffrey E. Dahl, L.t. Chapin, W.m. Moseley, Michael S. Allen, Ha TuckerAbstract:Abstract Holstein cows received 12mg/d of growth hormone-Releasing Factor (continuous i.v. infusion, n=5), 14mg/d of bST (single daily i.m. injection, n=8), or no treatment (controls, n=8) for 60 d. Compared with controls (31.6kg/d), bST and growth hormone-Releasing Factor increased milk yield to 34.2 and 37.0kg/d, respectively. The increase in milk yield induced by the growth hormone-Releasing Factor was greater than that for bST. Milk yield was not different among groups following cessation of treatment. Milk energy output was 24.2Mcal/d in controls, and growth hormone-Releasing Factor increased milk energy output to 28.5Mcal/d. Milk energy output of cows receiving bST was 26.1Mcal/d. Growth hormone-Releasing Factor increased DMI (23.2kg/d) over that of controls (21.1kg/d), whereas bST (21.5kg/d) did not. Relative to controls, bST increased averaged daily serum somatotropin from 1.3 to 7.6ng/ml and insulin-like growth Factor-I from 67.5 to 116.0ng/ml. Relative to bST, growth hormone-Releasing Factor increased serum somatotropin to 16.3ng/ml and insulin-like growth Factor-I to 202.6ng/ml. Relative to control (115.8meq/dl) and bST (158.1meq/dl), growth hormone-Releasing Factor increased plasma NEFA (230.3meq/dl). During treatment, calculated energy balance was negative for cows receiving growth hormone-Releasing Factor but positive for bST and control cows. Milk composition, body condition score, BW, and apparent digestibility of DM were not different among treatments. We conclude that i.v. infusion of 12mg/d mg of growth hormone-Releasing Factor has greater galactopoietic activity than i.m. injections of 14mg/d of bST. These data support the concept that the galactopoietic effects of growth hormone-Releasing Factor are mediated via increased secretion of somatotropin and insulin-like growth Factor-I.
E. Merlo Pich - One of the best experts on this subject based on the ideXlab platform.
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Learning impairment in transgenic mice with central overexpression of corticotropin-Releasing Factor.
Neuroscience, 1996Co-Authors: Stephen C. Heinrichs, Wylie Vale, George F. Koob, Mary P. Stenzel-poore, Lisa H. Gold, Elena Battenberg, Floyd E. Bloom, E. Merlo PichAbstract:Abstract The present studies were designed to test the learning and memory capacities of transgenic mice with central overexpression of corticotropin-Releasing Factor in a forced alternation water T-maze task and in the Morris water maze. In T-maze testing, littermate control mice reached a criterion of 70% correct responses after five days of trials, while the performance of transgenic subjects was still random after the same training. In Morris maze testing, control subjects reached the submerged platform significantly faster [ F (1,48) = 4.51, P F (4,40) = 16.61, P These results suggest that corticotropin-Releasing Factor- overexpressing mice subjects exhibit a profound learning deficit without sensory or motor-related impairments, and that memory plasticity can be restored by anxiolytic pre-treatment. Thus, constitutive overabundance of brain corticotropin-Releasing Factor may produce hyperemotionality that interferes with learned behaviors. Stress-related disorders characterized by co-morbid deficits in learning/memory may benefit from pharmacological normalization of brain corticotropin-Releasing Factor systems.
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Corticotropin-Releasing Factor release from the mediobasal hypothalamus of the rat as measured by microdialysis
Neuroscience, 1993Co-Authors: E. Merlo Pich, Wylie Vale, George F. Koob, Markus Heilig, Frédérique Menzaghi, Friedbert WeissAbstract:Procedures were developed to permit the measurement of corticotropin-Releasing Factor in perfusate collected from microdialysis probes implanted in various brain areas of anesthetized and awake rats. Initially in vitro experiments were carried out to optimize the recovery of corticotropin-Releasing Factor and the radioimmunoassay conditions. Addition of a specific antiserum against corticotropin-Releasing Factor to the perfusion medium (artificial cerebrospinal fluid) increased the relative in vitro recovery over a range of different flow rates (1-10 microliters/min) using commercially available microdialysis probes with a membrane cutoff of 20,000 mol. wt. This procedure increased recovery from 3% to 6% at flow rate of 2.5 microliters/min, and from 4% to 8% at a flow rate of 5 microliters/min. In vivo experiments were performed with a flow rate of 3.3 microliters/min and 50-microliters fractions were used for radioimmunoassay. In each experiment, the standard curve of the radioimmunoassay was constructed from aliquots of the same medium used to perfuse the probe. Basal levels of corticotropin-Releasing Factor in dialysate collected from the mediobasal hypothalamus of anesthetized rats were estimated to be 0.75 +/- 0.07 fmol/50 microliters. Raising the concentration of potassium (60 mM) in the perfusate increased corticotropin-Releasing Factor levels to 2.04 +/- 0.37 fmol/50 microliters. Hypertonic stress induced by intraperitoneal injection of 1.5M NaCl (20 ml/kg) elevated the levels to 1.32 +/- 0.07 fmol/50 microliters. A marked increase of corticotropin-Releasing Factor levels was also produced by a 10-min pulse of the potassium-channel blocker 4-aminopyridine (10 mM) included in the perfusate. A second stimulation pulse with 4-aminopyridine, administered 2 h after the first pulse again increased the levels, with a mean ratio between the first and second pulse of 0.97. Corticotropin-Releasing Factor efflux produced by the second stimulation pulse was completely inhibited by perfusion with calcium-free medium containing calcium-chelating agent ethyleneglycol tetraacetic acid (10 mM). In separate experiments, microdialysis probes were implanted in several brain areas of anesthetized rats. Basal and potassium-evoked levels of corticotropin-Releasing Factor were measured in dialysate collected from the amygdala (1.20 +/- 0.22 and 2.05 +/- 0.48 fmol/50 microliters, respectively) and frontal cortex (0.51 +/- 0.10 and 1.64 +/- 0.15 fmol/50 microliters, respectively). Corticotropin-Releasing Factor levels in the dorsal part of the third ventricle and in the striatum were below the detection limits. In awake rats, corticotropin-Releasing Factor levels in the mediobasal hypothalamus were 0.98 +/- 0.03 fmol/50 microliters.(ABSTRACT TRUNCATED AT 400 WORDS)
Donald R. Gehlert - One of the best experts on this subject based on the ideXlab platform.
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Differential distribution of urocortin- and corticotropin-Releasing Factor-like immunoreactivities in the rat brain
Neuroscience, 1999Co-Authors: S.m. Morin, N. Ling, S.d. Kahl, Donald R. GehlertAbstract:Abstract Urocortin, a novel 40 amino acid neuropeptide, is a member of the corticotropin-Releasing Factor family. With 45% homology to corticotropin-Releasing Factor, urocortin binds with similar affinity to the corticotropin-Releasing Factor-1 and corticotropin-Releasing Factor-2 receptors and may play a role in modulating many of the same systems as corticotropin-Releasing Factor. To assess whether urocortin and corticotropin-Releasing Factor are localized in the same regions of the brain, we compared the distribution of urocortin- and corticotropin-Releasing Factor-like immunoreactivities in the rat central nervous system. Polyclonal antibodies to rat corticotropin-Releasing Factor and rat urocortin were generated and utilized to map the distribution of corticotropin-Releasing Factor- and urocortin-like immunoreactivities throughout the rat forebrain and brainstem. Characterization of the antibodies by radioimmunoassay showed no cross-reactivity with related peptides. Male Sprague–Dawley rats were treated with colchicine for 18–24 h. Following colchicine treatment, the rats were perfused with paraformaldehyde–lysine–periodate fixative and their brains removed. Serial coronal sections were taken throughout the rat brain and processed for either corticotropin-Releasing Factor- or urocortin-like immunoreactivity. Urocortin-like immunoreactivity shows a discrete localization within several regions including the supraoptic nucleus, the median eminence, Edinger–Westphal nucleus and the sphenoid nucleus. This is in contrast to the more abundant corticotropin-Releasing Factor-like immunoreactivity. Regions containing high levels of corticotropin-Releasing Factor immunoreactivity include the lateral septum, paraventricular nucleus of the hypothalamus, median eminence and locus coeruleus. There are a few regions that contain both urocortin-immunoreactive and corticotropin-Releasing Factor-immunoreactive cells, such as the supraoptic nucleus and the hippocampus. Therefore, urocortin and corticotropin-Releasing Factor appear to have different distribution patterns which may be indicative of their respective physiological functions.
Fiona H Marshall - One of the best experts on this subject based on the ideXlab platform.
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structure of class b gpcr corticotropin Releasing Factor receptor 1
Nature, 2013Co-Authors: Kaspar Hollenstein, James Kean, Andrea Bortolato, Robert K Y Cheng, A S Dore, Ali Jazayeri, Robert M Cooke, Malcolm Peter Weir, Fiona H MarshallAbstract:Structural analysis of class B G-protein-coupled receptors (GPCRs), cell-surface proteins that respond to peptide hormones, has been restricted to the amino-terminal extracellular domain, thus providing little understanding of the membrane-spanning signal transduction domain. The corticotropin-Releasing Factor receptor type 1 is a class B receptor which mediates the response to stress and has been considered a drug target for depression and anxiety. Here we report the crystal structure of the transmembrane domain of the human corticotropin-Releasing Factor receptor type 1 in complex with the small-molecule antagonist CP-376395. The structure provides detailed insight into the architecture of class B receptors. Atomic details of the interactions of the receptor with the non-peptide ligand that binds deep within the receptor are described. This structure provides a model for all class B GPCRs and may aid in the design of new small-molecule drugs for diseases of brain and metabolism.
