Antagonism of corticotrophin-releasing factor receptors in the fourth ventricle modifies responses to mild but not restraint stress

Miragaya, Joanna; Harris, Ruth B. S.

doi:10.1152/ajpregu.00565.2007

Cited by 16 publications

(8 citation statements)

References 56 publications

(76 reference statements)

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“…Experiment 1: fourth-ventricle leptin dose response. Sixty-four rats were fitted with fourth-ventricle infusion cannula, as described previously (20). Daily body weights and food intakes were recorded for 1 wk, and then the rats were divided into seven weight-matched groups.…”

Section: Methodsmentioning

confidence: 99%

Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3

Harris

Desai

2016

American Journal of Physiology-Endocrinology and Metabolism

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Previous studies have shown that very low-dose infusions of leptin into the third or the fourth ventricle alone have little effect on energy balance, but simultaneous low-dose infusions cause rapid weight loss and increased phosphorylation of STAT3 (p-STAT3) in hypothalamic sites that express leptin receptors. Other studies show that injecting high doses of leptin into the fourth ventricle inhibits food intake and weight gain. Therefore, we tested whether fourth-ventricle leptin infusions that cause weight loss are associated with increased leptin signaling in the hypothalamus. In a dose response study 14-day infusions of increasing doses of leptin showed significant hypophagia, weight loss, and increased hypothalamic p-STAT3 in rats receiving at least 0.9 μg leptin/day. In a second study 0.6 μg leptin/day transiently inhibited food intake and reduced carcass fat, but had no significant effect on energy expenditure. In a final study, we identified the localization of STAT3 activation in the hypothalamus of rats receiving 0, 0.3, or 1.2 μg leptin/day. The high dose of leptin, which caused weight loss in the first experiment, increased p-STAT3 in the ventromedial, dorsomedial, and arcuate nuclei of the hypothalamus. The low dose that increased brown fat UCP1 but did not affect body composition in the first experiment had little effect on hypothalamic p-STAT3. We propose that hindbrain leptin increases the precision of control of energy balance by lowering the threshold for leptin signaling in the forebrain. Further studies are needed to directly test this hypothesis.

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Section: Methodsmentioning

confidence: 99%

Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3

Harris

Desai

2016

American Journal of Physiology-Endocrinology and Metabolism

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“…Thirty-five rats, housed as described above in a room maintained at 23°C, were each fitted with a 4th ventricle infusion cannula (Plastics One, Roanoake, VA) as described previously (27). The coordinates in relation to the midline at the occipital suture were 2.5 mm anterior, 0 mm lateral, and Ϫ6.5 mm ventral.…”

Section: Experiments 1: Effect Of a 4th Ventricle Low-dose Leptin Infumentioning

confidence: 99%

Leptin-induced increase in body fat content of rats

Harris

2013

American Journal of Physiology-Endocrinology and Metabolism

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Harris RB. Leptin-induced increase in body fat content of rats. Am J Physiol Endocrinol Metab 304: E267-E281, 2013. First published December 4, 2012; doi:10.1152/ajpendo.00251.2012.-We previously reported that peripheral leptin infusions in chronically decrebrate rats, in which the forebrain is neurally isolated from the hindbrain, increased body fat and decreased energy expenditure. Any central leptin response in decerebrate rats would depend upon the hindbrain. Here, we tested whether selective activation of hindbrain leptin receptors increased body fat. Fourth ventricle infusion of 0.6 g leptin/day for 12 days increased body fat by 13% with no increase in food intake. Third ventricle leptin infusions decreased food intake, body fat, and lean tissue with a maximal response at 0.3 g leptin/day. To test whether hindbrain receptors opposed activity of hypothalamic receptors, rats received peripheral infusions of 40 g leptin/day and increasing 4th ventricle doses of the leptin receptor antagonist mutein protein. Mutein (3.0 g/day) reduced body fat in PBS-infused rats to the same level as leptin-infused rats and reduced lean tissue in all rats. Leptin, but not mutein, inhibited food intake. By contrast, 3.0 g/day mutein in the 3rd ventricle increased food intake and body fat in both PBS-and leptin-infused rats. In basal conditions, hindbrain leptin receptors may antagonize activity of forebrain receptors to protect lean and fat tissue, but there is no evidence for an anabolic role for hindbrain receptors when leptin is elevated. In a dietary study, rats increased energy intake when offered lard and 30% sucrose solution in addition to chow. Peripheral leptin infusion exaggerated the gain in body fat without altering energy intake confirming the potential for leptin to increase adiposity.forebrain; hindbrain; mutein leptin; body composition LEPTIN IS AN ADIPOSE-DERIVED HORMONE that is hypothesized to be a negative feedback signal in the regulation of energy balance (46). Central (12, 43) or peripheral (37) administration of leptin inhibits food intake of normal-weight rodents and corrects many aspects of the obesity syndrome in leptin-deficient ob/ob mice (20, 33). The negative energy balance associated with peripheral leptin treatment results in a specific loss of body fat mass and maintenance of lean body mass (20); by contrast, central administration of leptin may result in the loss of both fat and lean tissue (5). Even though leptin is an effective regulator of energy balance in normal-weight rodents, obese or aged animals have high circulating concentrations of endogenous leptin but are leptin resistant because leptin administration does not influence food intake or body weight (7,9,44,45).Early observations that peripheral leptin resistance preceded the development of central leptin resistance in high-fat-fed mice (9) led to the conclusion that peripheral leptin resistance results from a failure of leptin to cross the blood-brain barrier (1), whereas central leptin resistance is a failure of leptin to activate ...

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“…2002, McCarthy et al . 1999, Miragaya & Harris 2008). CRH, along with arginine vasopressin (AVP) stimulates adrenocorticotropic hormone (ACTH) release from the pituitary, leading to increases in cortisol (corticosterone in rodents) secretion from the adrenal glands.…”

Section: Introductionmentioning

confidence: 99%

Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors

Lutfy

Aimiuwu

Mangubat

et al. 2012

Journal of Neurochemistry

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Corticosterone–releasing hormone (CRH) and arginine vasopressin (AVP) are crucial components of the hypothalamic-pituitary-adrenal (HPA) axis that stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary and mediate the stress response. CRH binds to two subtypes of CRH receptors (CRH-R1 and CRH-R2) that are present in both central and peripheral tissues. We used the CRH-R1 specific antagonist, antalarmin (ANT), the CRH-R1 and CRH-R2 peptide antagonist, astressin (AST), and the CRH-R2 specific peptide antagonist, astressin2b (AST2b), to determine which CRH receptor is involved in the nicotine-stimulated secretion of corticosterone. Male C57BL/6 mice were administered ANT (20 mg/kg, i.p.), AST (0.3 mg/kg, i.p.), AST2b (0.3 mg/kg, i.p.) or vehicle prior to administration of nicotine (1.0 mg/kg, s.c.), CRH (10 μg/kg, s.c.), AVP (10 μg/kg, s.c.) or saline (SAL) (s.c.), sacrificed 15 min later and trunk blood collected and assayed for corticosterone plasma levels. We found that CRH enhanced corticosterone release, and this response was blocked by both AST and ANT. Nicotine also increased corticosterone secretion, but this effect persisted in the presence of either CRH antagonist. Furthermore, AST but not ANT or AST2b decreased corticosterone levels associated with stress of handling and injection. We also assessed the role of AVP V1b specific receptor antagonist, SSR149415 alone and in combination with AST and AST2b. Although the AVP antagonist did not alter basal or nicotine-stimulated corticosterone secretion, it attenuated the AVP-induced stimulation of corticosterone and its combination with AST but not AST2b completely abolished nicotine-mediated stimulation of corticosterone secretion. Our results demonstrate that the nicotine-induced stimulation of the hypothalamic-pituitary adrenal axis (HPA) is mediated by both the CRH-R and the AVP V1b receptor and when the CRH receptor is blocked, nicotine may utilize the AVP V1b receptor to mediate secretion of corticosterone. These results argue in favor of the development of specific antagonists that block both AVP and CRH receptors to decrease the pleasurable component of nicotine, which may be mediated by corticosterone.

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Antagonism of corticotrophin-releasing factor receptors in the fourth ventricle modifies responses to mild but not restraint stress

Cited by 16 publications

References 56 publications

Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3

Fourth-ventricle leptin infusions dose-dependently activate hypothalamic signal transducer and activator of transcription 3

Leptin-induced increase in body fat content of rats

Nicotine stimulates secretion of corticosterone via both CRH and AVP receptors

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