Differential Distribution and Regulation of OX1 and OX2 Orexin/Hypocretin Receptor Messenger RNA in the Brain upon Fasting

Lü, Xin; Bagnol, Didier; Burke, Sharon; Akil, Huda; Watson, Stanley J.

doi:10.1006/hbeh.2000.1584

Cited by 275 publications

(192 citation statements)

References 38 publications

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“…These results clearly indicate that the TMN or its vicinity is a direct action site for the arousal effect of orexin A. It is also consistent with recent studies showing that the TMN is a putative wake center (36,43) with a dense distribution of orexin A immunoreactive processes (7,9,12) and the mRNA for orexin-2 receptors (24,25).…”

Section: Discussionsupporting

confidence: 92%

“…Despite their highly restricted origin, immunohistochemical studies have shown that orexin neurons project widely throughout the entire neuroaxis (6). Particularly abundant projections are found in monoaminergic cell groups, including histaminergic cells of the tuberomammillary nucleus (TMN) (7,14), in which orexin-2 receptors are enriched (24,25). It is well known that activation of the histaminergic system promotes wakefulness through activation of histamine H 1 receptor (H1R) (26)(27)(28).…”

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confidence: 99%

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Arousal effect of orexin A depends on activation of the histaminergic system

Huang

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

500

314

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Orexin neurons are exclusively localized in the lateral hypothalamic area and project their fibers to the entire central nervous system, including the histaminergic tuberomammillary nucleus (TMN). Dysfunction of the orexin system results in the sleep disorder narcolepsy, but the role of orexin in physiological sleep–wake regulation and the mechanisms involved remain to be elucidated. Here we provide several lines of evidence that orexin A induces wakefulness by means of the TMN and histamine H 1 receptor (H1R). Perfusion of orexin A (5 and 25 pmol/min) for 1 hr into the TMN of rats through a microdialysis probe promptly increased wakefulness for 2 hr after starting the perfusion by 2.5- and 4-fold, respectively, concomitant with a reduction in rapid eye movement (REM) and non-REM sleep. Microdialysis studies showed that application of orexin A to the TMN increased histamine release from both the medial preoptic area and the frontal cortex by ≈2-fold over the baseline for 80 to 160 min in a dose-dependent manner. Furthermore, infusion of orexin A (1.5 pmol/min) for 6 hr into the lateral ventricle of mice produced a significant increase in wakefulness during the 8 hr after starting infusion to the same level as the wakefulness observed during the active period in wild-type mice, but not at all in H1R gene knockout mice. These findings strongly indicate that the arousal effect of orexin A depends on the activation of histaminergic neurotransmission mediated by H1R.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Arousal effect of orexin A depends on activation of the histaminergic system

Huang

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

500

314

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“…Brain areas such the infralimbic cortex, hippocampus, and locus coeruleus exhibit high expression of OX 1 R, whereas OX 2 R is the only receptor expressed in arcuate nucleus, tuberomammillary nucleus, and dorsomedial and lateral hypothalamus (LH). Both receptors are present in the prefrontal cortex, amygdala, bed nucleus of stria terminalis, paraventricular thalamic nucleus, dorsal raphe, ventral tegmental area (VTA), and laterodorsal tegmental nucleus-peduncolo pontine nucleus (Lu et al, 2000;Marcus et al, 2001;Trivedi et al, 1998). These findings suggest that OXs and their receptors are likely to play a broad regulatory role in the central nervous system.…”

Section: Introductionmentioning

confidence: 97%

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Piccoli

Bonaventura

Cifani

et al. 2012

Neuropsychopharmacol

141

102

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Orexins (OX) and their receptors (OXR) modulate feeding, arousal, stress, and drug abuse. Neural systems that motivate and reinforce drug abuse may also underlie compulsive food seeking and intake. Therefore, the effects of GSK1059865, a dual OX 1 /OX 2 R antagonist were evaluated in a binge eating (BE) model in female rats. BE of highly palatable food (HPF) was evoked by three cycles of food restriction followed by stress, elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Pharmacokinetic assessments of all compounds were obtained under the same experimental conditions used for the behavioral experiments. Topiramate was used as the reference compound as it selectively blocks BE in rats and humans. Dose-related thresholds for sleep-inducing effects of the OXR antagonists were measured using polysomnography in parallel experiments. SB-649868 and GSK1059865, but not JNJ-10397049, selectively reduced BE for HPF without affecting standard food pellet intake, at doses that did not induce sleep. These results indicate, for the first time, a major role of OX 1 R mechanisms in BE, suggesting that selective antagonism at OX 1 R could represent a novel pharmacological treatment for BE and possibly other eating disorders with a compulsive component.

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“…Early studies indicated that VMH lesions resulted in hyperphagia and obesity (28,38,66), whereas electrical stimulation of the VMH immediately suppressed feeding and induced lipolysis (65). Glucose-sensing neurons (7,27,55,74,75) and receptors for neuropeptides important to energy metabolism have been identified in the VMH, including leptin (13,17,20,22,51), melanocortin (26), neuropeptide Y (NPY) (43), corticotrophin-releasing hormone (49), CCK (12), insulin (33), and orexin (44) receptors. Many biological agents given into the VMH have been demonstrated to affect feeding.…”

mentioning

confidence: 99%

Brain-derived neurotrophic factor in the ventromedial nucleus of the hypothalamus reduces energy intake

Wang

Bomberg²,

Levine³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent studies show that brainderived neurotrophic factor (BDNF) decreases feeding and body weight after peripheral and ventricular administration. BDNF mRNA and protein, and its receptor TrkB, are widely distributed in the hypothalamus and other brain regions. However, there are few reports on specific brain sites of actions for BDNF. We evaluated the effect of BDNF, given into the ventromedial nucleus of the hypothalamus (VMH), on normal and deprivation-and neuropeptide Y (NPY)-induced feeding behavior and body weight. BDNF injected unilaterally or bilaterally into the VMH of food-deprived and nondeprived rats significantly decreased feeding and body weight gain within the 0-to 24-h and the 24-to 48-h postinjection intervals. Doses effectively producing inhibition of feeding behavior did not establish a conditioned taste aversion. BDNF-induced feeding inhibition was attenuated by pretreatment of the TrkB-Fc fusion protein that blocks binding between BDNF and its receptor TrkB. VMH-injected BDNF significantly decreased VMH NPY-induced feeding at 1, 2, and 4 h after injection. In summary, BDNF in the VMH significantly decreases food intake and body weight gain, by TrkB receptor-mediated actions. Furthermore, the anorectic effects of BDNF in this site appear to be mediated by NPY. These data suggest that the VMH is an important site of action for BDNF in its effects on energy metabolism. food intake; body weight THE VENTROMEDIAL NUCLEUS OF THE HYPOTHALAMUS (VMH) is a brain area important to the regulation of energy metabolism. Early studies indicated that VMH lesions resulted in hyperphagia and obesity (28,38,66), whereas electrical stimulation of the VMH immediately suppressed feeding and induced lipolysis (65). Glucose-sensing neurons (7,27,55,74,75) and receptors for neuropeptides important to energy metabolism have been identified in the VMH, including leptin (13,17,20,22,51), melanocortin (26), neuropeptide Y (NPY) (43), corticotrophin-releasing hormone (49), CCK (12), insulin (33), and orexin (44) receptors. Many biological agents given into the VMH have been demonstrated to affect feeding. Food intake is inhibited by administration of histamine (4, 47), glucagon-like peptide 1 (70), serotonin agonists (25), urocortin (58), CCK (79), leptin (51), and insulin (78), whereas thyroid hormone (3,5,3Ј-triiodothyronine) (40), GABA or GABA agonists (32,34,35), norepinephrine (73), orexin (74), and NPY induce feeding after administration into the VMH (5,9,24,31,43,56,76).Anatomically, the VMH receives inputs from regions important to the regulation of energy metabolism, including the hypothalamic arcuate nucleus (ARC) (2, 14, 23), lateral hypothalamus (18, 67, 80), amygdala (45, 50), and lateral septum. The VMH also projects to ARC (77), paraventricular nucleus (PVN) (42, 52), lateral hypothalamus (72, 80), dorsomedial nucleus of the hypothalamus (46, 80), amygdala (6, 68), lateral septum (68), ventral tegmental area (68), nucleus accumbens (6), and nucleus of the solitary tract (6). These behavioral and neuroanatom...

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Differential Distribution and Regulation of OX1 and OX2 Orexin/Hypocretin Receptor Messenger RNA in the Brain upon Fasting

Cited by 275 publications

References 38 publications

Arousal effect of orexin A depends on activation of the histaminergic system

Arousal effect of orexin A depends on activation of the histaminergic system

Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats

Brain-derived neurotrophic factor in the ventromedial nucleus of the hypothalamus reduces energy intake

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