SB‐334867‐A: the first selective orexin‐1 receptor antagonist

Smart, Darren; Sabido-David, Cibele; Brough, Stephen; Jewitt, F; Johns, Amanda; Porter, Rod A.; Jerman, Jeffrey C.

doi:10.1038/sj.bjp.0703953

Cited by 294 publications

(223 citation statements)

References 10 publications

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“…To further investigate whether Hcrt signaling to LC neurons is necessary for Hcrt-mediated sleep-to-wake transitions, we repeated photostimulation experiments in Hcrt::ChR2-mCherry and Hcrt::mCherry control animals (15-ms pulses at 1 or 10 Hz for 10 s) 15 min after bilateral injection of a Hcrt receptor antagonist, SB-334867 (27), directly into the LC region. Stimulation of ChR2-mCherry animals at 10 Hz significantly reduced the sleep-to-wake latency compared with that in animals stimulated at 1 Hz or in mCherry control animals (P < 0.0001, n = 4 animals per condition), but this effect was blocked following microinjection of 100 μM SB-334867 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanism for Hypocretin-mediated sleep-to-wake transitions

Carter

Brill

Bonnavion³

et al. 2012

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

248

203

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Current models of sleep/wake regulation posit that Hypocretin (Hcrt)-expressing neurons in the lateral hypothalamus promote and stabilize wakefulness by projecting to subcortical arousal centers. However, the critical downstream effectors of Hcrt neurons are unknown. Here we use optogenetic, pharmacological, and computational tools to investigate the functional connectivity between Hcrt neurons and downstream noradrenergic neurons in the locus coeruleus (LC) during nonrapid eye movement (NREM) sleep. We found that photoinhibiting LC neurons during Hcrt stimulation blocked Hcrt-mediated sleep-to-wake transitions. In contrast, when LC neurons were optically stimulated to increase membrane excitability, concomitant photostimulation of Hcrt neurons significantly increased the probability of sleep-to-wake transitions compared with Hcrt stimulation alone. We also built a conductance-based computational model of Hcrt-LC circuitry that recapitulates our behavioral results using LC neurons as the main effectors of Hcrt signaling. These results establish the Hcrt-LC connection as a critical integrator-effector circuit that regulates NREM sleep/wake behavior during the inactive period. This coupling of distinct neuronal systems can be generalized to other hypothalamic integrator nuclei with downstream effector/output populations in the brain.ChR2 | norepinephrine | step function opsin T he neural basis of wakefulness and arousal is thought to depend on subcortical populations of "arousal-promoting" nuclei located in the hypothalamus and brainstem (1, 2). Neurons in the lateral hypothalamus that express hypocretins (Hcrts-also called "orexins"), a pair of neuropeptides produced from the same genetic precursor (3, 4), have been proposed to play a key role in stabilizing wake states by directly projecting throughout the brain to other arousal populations (1,5,6). Electrophysiological recordings of Hcrt neurons show that they are relatively silent during sleep compared with wakefulness, with phasic bursts of activity preceding transitions to wakefulness (7,8). Loss-of-function perturbation of the Hcrts or their receptors causes a narcolepsy phenotype (9-11). When centrally administered, the Hcrts increase the time spent awake and decrease nonrapid eye movement (NREM) and rapid eye movement (REM) sleep (12, 13).Although it is evident that Hcrts promote wakefulness and arousal, it is unknown which downstream structures are necessary and/or sufficient to mediate their effects. Hcrt neurons project diffusely throughout the brain (14), and it is possible that their effects on wakefulness are due to widespread, global postsynaptic targets. Alternatively, Hcrts may affect arousal primarily by projecting to key downstream arousal centers. An intriguing possibility is that Hcrt neurons affect wakefulness by projecting to the locus coeruleus (LC), a noradrenergic structure in the brainstem known to promote wakefulness and arousal (15, 16). Indeed, the LC receives the densest afferent projections from Hcrt neurons (14, 17). Application o...

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Section: Resultsmentioning

confidence: 99%

Mechanism for Hypocretin-mediated sleep-to-wake transitions

Carter

Brill

Bonnavion³

et al. 2012

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

248

203

View full text Add to dashboard Cite

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“…Orexin containing neurons are inactive in sleep and maximally active in waking states characterized by exploratory activity (Lee et al, 2005;Mileykovskiy et al, 2005). Recently, the importance of this endogenous system for sleep cycle regulation was demonstrated by the use of the selective orexin receptor antagonists, including ACT-078573 (Actelion Pharmaceuticals), in rodents, dogs, and man (Smart et al, 2001;Soffin et al, 2002;Brisbare-Roch et al, 2007;Rasmussen et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates

Deadwyler¹,

Porrino²,

Siegel³

et al. 2007

J. Neurosci.

239

192

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Hypocretin-1 (orexin-A) was administered to sleep-deprived (30 -36 h) rhesus monkeys immediately preceding testing on a multi-image delayed match-to-sample (DMS) short-term memory task. The DMS task used multiple delays and stimulus images and effectively measures cognitive defects produced by sleep deprivation (Porrino et al., 2005). Two methods of administration of orexin-A were tested, intravenous injections (2.5-10.0 g/kg, i.v.) and a novel method developed for nasal delivery via an atomizer spray mist to the nostrils (dose estimated 1.0 g/kg). Results showed that orexin-A delivered via the intravenous and nasal routes significantly improved performance in sleep-deprived monkeys; however, the nasal delivery method was significantly more effective than the highest dose (10 g/kg) of intravenous orexin-A tested. The improvement in performance by orexin-A was specific to trials classified as high versus low cognitive load as determined by performance difficulty under normal testing conditions. Except for the maximum intravenous dose (10 g/kg), neither delivery method affected task performance in alert non-sleep-deprived animals. The improved performance in sleep-deprived animals was accompanied by orexin-A related alterations in local cerebral glucose metabolism (CMRglc) in specific brain regions shown previously to be engaged by the task and impaired by sleep deprivation (Porrino et al., 2005). Consistent with the differential effects on performance, nasal delivered orexin-A produced a more pronounced reversal of sleep deprivation induced changes in brain metabolic activity (CMRglc) than intravenous orexin-A. These findings provide strong evidence for the effectiveness of intranasal orexin-A in alleviating cognitive deficits produced by loss of sleep.

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“…SB-334867 is a non-peptide selective OX1R antagonist [34], and it made it possible to examine a physiological role of orexin-OX1R pathways in 13 the biological actions. Bülbül et al [13,18] Based upon these lines of evidence, Figure 9 reveals the schematic illustration of our hypothesis on the mechanism by which orexin-A acts in the brain to stimulate gastric motility.…”

Section: Discussionmentioning

confidence: 99%