Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies have shown that acute systemic administration of the selective orexin-1 receptor antagonist SB-334867 significantly reduces food intake in rats. Although this anorectic action of orexin-1 receptor blockade is associated with an acceleration in the transition from eating to resting, it is widely recognised that the behavioural indices of satiety are not dissimilar to those of illness. In this context, Experiment 1 confirmed a significant anorectic effect of 90 (but not 60) mg/kg lithium chloride (LiCl) in male rats presented with palatable mash in the home-cage environment. Experiment 2 employed a continuous monitoring technique to contrast the effects of LiCl (90 mg/kg) and SB-334867 (10 and 30 mg/kg) on food intake and behaviour during a 1-h test with palatable mash. SB-334867 dose-dependently inhibited food intake, with the higher dose producing a comparable degree of appetite suppression (approximately 40%) to that seen with LiCl. Despite equivalent anorectic action, the two compounds produced very different effects on behaviour. LiCl reduced active behaviours (locomotion, rearing, grooming and sniffing), slowed the rate of eating and disrupted the behavioural satiety sequence (BSS). In contrast, SB-334867 (30 mg/kg) decreased the duration of feeding and grooming, and modestly accelerated the transition between eating and resting. Furthermore, whereas LiCl failed to alter posttreatment bodyweight gain, SB-334867 (30 mg/kg) produced a significant weight loss in the 24-h period immediately following injection. Overall, the divergent profiles obtained with equianorectic doses of LiCl and SB-334867 provide convincing evidence for the behavioural selectivity of SB-334867-induced anorexia.
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PMID:Differential effects of the selective orexin-1 receptor antagonist SB-334867 and lithium chloride on the behavioural satiety sequence in rats. 1505 92

Narcolepsy is caused by a lack of orexin (hypocretin), but the physiologic process that underlies the sleepiness of narcolepsy is unknown. Using orexin knock-out (KO) mice as a model of narcolepsy, we critically tested the three leading hypotheses: poor circadian control of sleep and wakefulness, inadequate activation of arousal regions, or abnormal sleep homeostasis. Compared with wild-type (WT) littermates, orexin KO mice had essentially normal amounts of sleep and wake, but wake and non-rapid eye movement (NREM) bouts were very brief, with many more transitions between all behavioral states. In constant darkness, orexin KO mice had normal amplitude and timing of sleep-wake rhythms, providing no evidence for disordered circadian control. When placed in a new, clean cage, both groups of mice remained awake for approximately 45 min, demonstrating that, even in the absence of orexin, fundamental arousal regions can be engaged to produce sustained wakefulness. After depriving mice of sleep for 2-8 hr, orexin KO mice recovered their NREM and rapid eye movement sleep deficits at comparable rates and to the same extent as WT mice, with similar increases in EEG delta power, suggesting that their homeostatic control of sleep is normal. These experiments demonstrate that the fragmented wakefulness of orexin deficiency is not a consequence of abnormal sleep homeostasis, poor circadian control, or defective fundamental arousal systems. Instead, the fragmented behavior of orexin KO mice may be best described as behavioral state instability, with apparently low thresholds to transition between states.
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PMID:Behavioral state instability in orexin knock-out mice. 1525 84

Acute systemic treatment with the selective orexin-1 receptor antagonist SB-334867 (30 mg/kg, i.p.) has been reported not only to inhibit food intake and to accelerate behavioural satiety in rats, but also to produce a significant loss of bodyweight over the 24 h period post-dosing. The present studies were designed to test the hypothesis that the inhibition of weight gain following acute treatment with SB-334867 is due to a persistent anorectic action of the compound. In Experiment 1, the acute effects of SB-334867 (30 mg/kg, i.p.) on food intake and behaviour in a 1 h test with palatable mash were assessed as a function of injection-test interval. Results confirmed that, when administered 30 min prior to testing, SB-334867 significantly suppressed mash intake and accelerated behavioural satiety. More importantly, significant anorexia and behavioural change were also observed when animals were tested 24 h, but not 48 h, post-dosing. As previously reported, all animals treated with the orexin-1 receptor antagonist lost bodyweight over the 24 h period following acute treatment. The generality of these findings was confirmed in Experiment 2, where acute treatment with SB-334867 (30 mg/kg, i.p.) significantly suppressed home cage chow consumption over the 24 h period post-dosing, an effect also accompanied by a significant loss of bodyweight. The results of Experiment 3 showed that, following i.p. administration of 30 mg/kg, SB-334867 has good CNS penetration, reaches peak plasma and brain concentrations at 30 min, and maintains good exposure over 4 h post-dosing. Overall, current data support the hypothesis that a persistent anorectic action contributes to the significant loss of bodyweight observed 24 h following acute dosing with SB-334867. As the compound is virtually undetectable in plasma or brain beyond 8 h post-dosing, and since nothing is known about potentially active metabolites, we consider the possibility that single dose treatment with SB-334867 results in enduring alterations to the orexin-1 receptor and/or downstream signalling pathways.
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PMID:Anorexia and weight loss in male rats 24 h following single dose treatment with orexin-1 receptor antagonist SB-334867. 1563 84

The ingestion of foods is comprised of two distinct phases of behavior: appetitive and consummatory. While most food intake paradigms include both phases, the intraoral intake test emphasizes the stereotyped consummatory-phase by infusing a liquid food directly into the oral cavity. Several hypothalamic peptides have been shown to increase intake of chow in standard food intake paradigms and the current experiments sought to test whether these peptides would increase food intake in the intraoral intake paradigm. NPY, melanin-concentrating hormone (MCH) and orexin-A were infused into the third ventricle (i3vt) in a counterbalanced latin-square design just prior to rats getting 0.1M sucrose solution infused via indwelling intraoral catheters and compared it to intake on bottle tests with access to the same sucrose solution. On the first day, each peptide increased intraoral intake relative to saline in the between-subjects comparison. Moreover, intake of sucrose following i3vt saline increased as a function of training. By the final day of the experiment, rats receiving saline consumed as much sucrose as rats receiving NPY, MCH, or orexin-A. This finding was conceptually replicated in the second experiment in which rats drank sucrose freely from a bottle on the home cage. A third experiment directly assessed the role of previous exposure in the sucrose intake induced by NPY. Those results confirm that repeated exposure to sucrose increases baseline intake and attenuates the hyperphagic effect of NPY. These results are consistent with two conclusions: (1) NPY, MCH, and orexin-A increase both appetitive and consummatory-phase ingestive behaviors on initial exposures; (2) repeated training interacts with the effects of these orexigenic peptides.
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PMID:The role of previous exposure in the appetitive and consummatory effects of orexigenic neuropeptides. 1580 5

Previous studies have shown that central alpha1-adrenoceptor activity is necessary, acutely, for gross behavioral activity in response to novel surroundings and various psychostimulants. The present experiment tested whether it is also necessary for the hyperactivity produced by the peptide, orexin A, which is present in several central monoaminergic nuclei. Mice, pretreated intraventricularly with the alpha1-antagonist, terazosin, or the alpha2-antagonist, atipamezole, were given orexin A, intraventricularly (i.v.t.), and videotaped for gross movement and locomotion in the home cage between 30 and 60 min post-infusion. The alpha1-antagonist was found to produce a significant dose-dependent decrease of orexin A-induced activity, which was first seen at the 3 nmol dose and was near total at 30 nmol. The alpha2-antagonist, at 10 nmol, had no effect on the orexin A response. Pharmacological inhibition of the synthesis of epinephrine, a potential neurotransmitter at central motoric alpha1-adrenoceptors, with 2,3-dichloro-alpha-methylbenzylamine also significantly attenuated orexin A-induced hyperactivity. It is concluded that central alpha1-adrenoceptor activity, presumably caused by epinephrine release, is necessary for the gross behavioral activation produced by orexin A.
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PMID:Evidence of roles of central alpha1-adrenoceptors and epinephrine in orexin A-induced hyperactivity in mice. 1589 93

Hypocretin (Hcrt, also known as orexin) is a hypothalamic neuropeptide linked to narcolepsy, a disorder diagnosed by the appearance of rapid eye-movement sleep (REMS)-state characteristics during waking. Major targets of Hcrt-containing fibers include the locus coeruleus and the raphe nucleus, areas with important roles in regulation of mood and sleep. A relationship between REMS and mood is suggested by studies demonstrating that REMS-deprivation (REMSD) ameliorates depressive symptoms in humans. Additional support is found in animal studies where antidepressants and REMSD have similar effects on monoamiergic systems thought to be involved in major depression. Recently, we have reported that Wistar-Kyoto (WKY) rats, an animal model of depression, have reduced number and size of hypothalamic cells expressing Hcrt-immunoractivity compared to the parent, Wistar (WIS) strain, suggesting the possibility that the depressive-like attributes of the WKY rat may be determined by this relative reduction in Hcrt cells [Allard, J.S., Tizabi, Y., Shaffery, J.P., Trouth, C.O., Manaye, K., 2004. Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Neuropeptides 38, 311-315]. In this study, we sought to test the hypothesis that REMSD would result in a greater increase in the number and/or size of hypothalamic, Hcrt-immunoreactive (Hcrt-ir) neurons in WKY, compared to WIS rats. The effect of REMSD, using the multiple-small-platforms-over-water (SPRD) method, on size and number of Hcrt-ir cells were compared within and across strains of rats that experienced multiple-large-platforms-over-water (LPC) as well as to those in a normal, home-cage-control (CC) setting. In accord with previous findings, the number of Hcrt-ir cells was larger in all three WIS groups compared to the respective WKY groups. REMSD produced a 20% increase (p<0.02) in the number of hypothalamic Hcrt-ir neurons in WKY rats compared to cage control WKY (WKY-CC) animals. However, an unexpected higher increase in number of Hcrt-ir cells was also observed in the WKY-LPC group compared to both WKY-CC (31%, p<0.001) and WKY-SPRD (20%, p<0.002) rats. A similar, smaller, but non-significant, pattern of change was noted in WIS-LPC group. Overall the data indicate a differential response to environmental manipulations where WKY rats appear to be more reactive than WIS rats. Moreover, the findings do not support direct antidepressant-like activity for REMSD on hypothalamic Hcrt neurons in WKY rats.
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PMID:Effects of rapid eye movement sleep deprivation on hypocretin neurons in the hypothalamus of a rat model of depression. 1759 Apr 34

Previously, we reported that lateral hypothalamic (LH) orexin neurons are stimulated in proportion to the preference shown for reward-associated cues during conditioned place preference (CPP) testing. Here, we examine for the first time the role of these neurons in the acquisition of morphine CPP. Results show that LH orexin neurons, but not those in the perifornical area (PFA), are stimulated during conditioning when morphine is given in a novel drug-paired environment (CPP compartment) but not when given in the home cage, nor when saline was given in the CPP environment. Furthermore, bilateral excitotoxic lesions of the LH orexin area completely blocked the acquisition of morphine CPP. Lesions that spared LH orexin neurons had no effect. Orexin neurons in the LH project to the ventral tegmental area (VTA), an area important in the acquisition of morphine CPP. Therefore, we investigated the importance of the LH orexin connection to the VTA in the acquisition of a morphine CPP using a disconnection technique involving a unilateral excitotoxic lesion of LH orexin neurons and contralateral blockade of VTA orexin receptors. Results indicated that a unilateral LH orexin lesion together with a microinjection of the orexin A antagonist (SB 334867) into the contralateral VTA prior to each morphine-pairing session was sufficient to block the development of a morphine CPP. Either of these treatments by themselves was not sufficient to block CPP development. These results demonstrate the importance of LH orexin neurons and their projections to the VTA in the formation of associations between environmental cues and drug reward.
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PMID:Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward. 1759 78

Orexin neurons in the lateral hypothalamus constitute a critical component in regulation of waking, feeding, and reward-related behaviors. In this study we examined the effects of lipopolysaccharide (LPS) challenge on Fos expression in orexin neurons in rats, to determine changes during sickness in two different behavioral contexts. One cohort of rats was treated with saline or LPS during the daytime, and then tested on an elevated plus maze (EPM) or left in their home cage until sacrifice. Another cohort received LPS or saline shortly before dark onset and was sacrificed 90min into the dark period. The brains were double-stained for Fos and orexin-A immunoreactivity (both cohorts) and for Fos and histidine decarboxylase (dark period cohort). Orexin neurons were strongly activated in context of exploratory behavior (double-labeled for Fos in both medial and lateral portions). LPS challenge prior to maze exposure diminished this activation, most notably among the lateral orexin neurons. In home cage controls, LPS challenge lead to increased Fos expression, most notably in the medial orexin neurons, when compared to saline-injected home cage controls that show little or no Fos during the daytime. In the dark period, Fos expression in both orexin and histaminergic neurons was abundant, which LPS challenge strongly suppressed. These findings are consistent with the hypothesis that the orexin neurons, in conjunction with the histaminergic system, represent a potential target of the neurocircuitry that drives sickness behavior due to peripheral inflammation, likely through functional inhibition of these hypothalamic cell groups.
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PMID:Lipopolysaccharide challenge-induced suppression of Fos in hypothalamic orexin neurons: their potential role in sickness behavior. 1932 47

Orexin/hypocretin signaling at the orexin 1 receptor (OX(1)R) has recently been implicated in addiction and relapse. We examined the role of the orexin system in cocaine-seeking elicited by a drug-associated context following abstinence or extinction from chronic cocaine self-administration. Male Sprague-Dawley rats self-administered cocaine in 2-h sessions for 10 days, followed by extinction training or extended abstinence in the home cage. The OX(1)R antagonist SB-334867 (SB; 10, 20, or 30 mg/kg, i.p.) was administered prior to re-exposure to the cocaine self-administration environment. We found that pretreatment with SB significantly attenuated cocaine-seeking when rats were placed back into the self-administration environment following either 1 day or 2 weeks of abstinence (no extinction), or following extinction of cocaine-seeking in an alternative environment (distinct from the training environment). These results indicate that orexin signaling at OX(1)R is critical for conditioned cocaine-seeking elicited by a drug-associated context, following either extinction or abstinence.
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PMID:Orexin/hypocretin is necessary for context-driven cocaine-seeking. 1959 50

Sleep deprivation induces several negative effects on behavior, emotion, attention, and learning ability. Sleep appears to be particularly important during adolescent brain development. In the present study, we examined the effects of sleep deprivation on behavior and hypothalamic neurotransmission including histamine and orexin neurons in adolescent rats using the treadmill method. Adolescent male rats were divided into three groups: treadmill sleep-deprived, treadmill control, and cage control groups. Energy expenditure, anxiety-like behavior, and locomotor activity were examined among the three groups. Histamine concentration in the cortex and diencephalon and the number of c-Fos-positive neurons in the hypothalamus were also examined. In addition, histamine and orexin neurons in the hypothalamus were simultaneously identified using rat histidine decarboxylase and orexin-A immunohistochemistry, respectively. Both energy expenditure and anxiety-related behavior significantly increased by the experimental 3-day sleep deprivation, while exploratory locomotor activity significantly decreased. Histamine contents did not change in the cortex, but significantly decreased in the diencephalon of sleep-deprived rats. Increased expression of c-Fos-positive neurons, including subgroup histamine and orexin neurons, was observed in the hypothalamus. These findings indicate that sleep deprivation increases energy expenditure and anxiety in adolescent rats and provide evidence for the pivotal role of hypothalamus subgroup histamine and orexin neurons in the behavioral response to sleep deprivation.
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PMID:Roles of hypothalamic subgroup histamine and orexin neurons on behavioral responses to sleep deprivation induced by the treadmill method in adolescent rats. 2113 11


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