Orexins/hypocretins excite basal forebrain cholinergic neurones

Eggermann, Emmanuel; Serafin, Mauro; Bayer, Laurence; Machard, Danièle; Saint-Mleux, Benoı̂t; Jones, Barbara E.; Mühlethaler, Michel

doi:10.1016/s0306-4522(01)00512-7

Cited by 285 publications

(187 citation statements)

References 28 publications

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…All-known wake-promoting cell groups express HcrtRs and are innervated by Hcrt neurons Eggermann et al, 2001;Eriksson et al, 2001;Li et al, 2002;Marcus et al, 2001;Peyron et al, 1998;Yamanaka et al, 2002). If ALM were to promote sleep through inhibition of downstream targets, it would be expected to interfere with the activation of wake-promoting cell groups.…”

Section: Discussionmentioning

confidence: 99%

“…Hcrt neurons activate these brain regions (Carter et al, 2012;Eggermann et al, 2001;Eriksson et al, 2001;Liu et al, 2002;Schone et al, 2012) through the co-release of Hcrt, glutamate (GLU) (Schone et al, 2012), and dynorphin (Eriksson et al, 2004;Li et al, 2014;Muschamp et al, 2014). Hcrt neurons are active primarily during wakefulness (Lee et al, 2005), and extracellular Hcrt levels are highest during awakening and periods of heightened emotionality (Blouin et al, 2013), consistent with a role in the regulation of arousal.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

The dual hypocretin receptor (HcrtR) antagonist almorexant (ALM) may promote sleep through selective disfacilitation of wakepromoting systems, whereas benzodiazepine receptor agonists (BzRAs) such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. Previous studies have indicated that HcrtR antagonists cause less-functional impairment than BzRAs. To gain insight into the mechanisms underlying these differential profiles, we compared the effects of ALM and ZOL on functional activation of wake-promoting systems at doses equipotent for sleep induction. Sprague-Dawley rats, implanted for EEG/EMG recording, were orally administered vehicle (VEH), 100 mg/kg ALM, or 100 mg/kg ZOL during their active phase and either left undisturbed or kept awake for 90 min after which their brains were collected. ZOL-treated rats required more stimulation to maintain wakefulness than VEH-or ALM-treated rats. We measured Fos co-expression with markers for wake-promoting cell groups in the lateral hypothalamus (Hcrt), tuberomammillary nuclei (histamine; HA), basal forebrain (acetylcholine; ACh), dorsal raphe (serotonin; 5HT), and singly labeled Fos + cells in the locus coeruleus (LC). Following SD, Fos co-expression in Hcrt, HA, and ACh neurons (but not in 5HT neurons) was consistently elevated in VEH-and ALMtreated rats, whereas Fos expression in these neuronal groups was unaffected by SD in ZOL-treated rats. Surprisingly, Fos expression in the LC was elevated in ZOL-but not in VEH-or ALM-treated SD animals. These results indicate that Hcrt signaling is unnecessary for the activation of Hcrt, HA, or ACh wake-active neurons, which may underlie the milder cognitive impairment produced by HcrtR antagonists compared to ZOL.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…Studies on tegmental (Burlet et al, 2002) and preoptic (Eggermann et al, 2001) cholinergic neurons did not report the EC 50 values for Hcrt. Whether these differences in EC 50 values of Hcrt are caused by regional variations in the destruction of the Hcrt peptides by local peptidases or other factors remains unknown.…”

Section: Hcrt Excites Septohippocampal Cholinergic Neurons Via a Dirementioning

confidence: 98%

“…Thus, the present study provides the first definitive evidence for synaptic innervation of cholinergic neurons by Hcrt fibers in the brain. Excitatory effects of Hcrt on cholinergic neurons of the magnocellular preoptic nucleus (Eggermann et al, 2001) and the laterodorsal tegmental nucleus (Burlet et al, 2002) have been reported, although the underlying ionic mechanisms and their dependence on sodium or potassium has not been studied. Thus, evidence for positive interactions between Hcrt and cholinergic neurons of the brain that are involved in the sleep-wake cycle continues to build.…”

Section: Hcrt Innervation Of Septohippocampal Cholinergic Neuronsmentioning

confidence: 99%

“…Hcrt is excitatory to CNS neurons including those believed to be involved with arousal (Ivanov and Aston-Jones, 2000;Eggermann et al, 2001;Burlet et al, 2002;Korotkova et al, 2003). In a recent study we reported that septohippocampal GABAergic neurons are innervated by Hcrt-containing fibers, express Hcrt-R2, and are excited by Hcrts via activation of the Na ϩ -Ca 2ϩ exchanger .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Wu¹,

Záborszky²,

Hajszán³

et al. 2004

J. Neurosci.

131

101

View full text Add to dashboard Cite

Hypothalamic fibers containing the wake-promoting peptides, hypocretins (Hcrts) or orexins, provide a dense innervation to the medial septum-diagonal band of Broca (MSDB), a sleep-associated brain region that has been suggested to show intense axonal degeneration in canine narcoleptics. The MSDB, via its cholinergic and GABAergic projections to the hippocampus, controls the hippocampal theta rhythm and associated learning and memory functions. Neurons of the MSDB express very high levels of the Hcrt receptor 2, which is mutated in canine narcoleptics. In the present study, we investigated the electrophysiological effects of Hcrt peptides on septohippocampal cholinergic neurons that were identified in living brain slices of the MSDB using a selective fluorescent marker. Hcrt activation of septohippocampal cholinergic neurons was reversible, reproducible, and concentration dependent and mediated via a direct postsynaptic mechanism. Both Hcrt1 and Hcrt2 activated septohippocampal cholinergic neurons with similar EC 50 values. The Hcrt effect was dependent on external Na ϩ , reduced by external Ba 2ϩ , and also reduced in recordings with CsCl-containing electrodes, suggesting a dual underlying ionic mechanism that involved inhibition of a K ϩ current, presumably an inward rectifier, and a Na ϩ -dependent component. The Na ϩ component was dependent on internal Ca 2ϩ , blocked by replacing external Na ϩ with Li ϩ , and also blocked by bath-applied Ni 2ϩ and KB-R7943, suggesting involvement of the Na ϩ -Ca 2ϩ exchanger. Using double-immunolabeling studies at light and ultrastructural levels, we also provide definitive evidence for a hypocretin innervation of cholinergic neurons. Thus Hcrt effects within the septum should increase hippocampal acetylcholine release and thereby promote hippocampal arousal.

show abstract

Hypocretin/Orexin System

Sutcliffe

Lecea

2007

Handbook of Contemporary Neuropharmacology

View full text Add to dashboard Cite

The hypocretins (also called the orexins) are excitatory neurotransmitters produced in a few thousand neurons of the lateral hypothalamus. Two G protein‐coupled receptors for the hypocretins have different distributions within the CNS and differential affinities for the two hypocretin peptides. Hypocretins efferents project to areas within the posterior hypothalamus that are implicated in feeding behaviors and hormone secretion. Hypocretin fibers also project to diverse targets in other brain regions and the spinal cord, including several areas implicated in cardiovascular function and sleep‐wake regulation. Administration of the hypocretins stimulates food intake, affects blood pressure, hormone secretion and locomotor activity, and increases wakefulness while suppressing rapid eye movement (REM) sleep. Narcolepsy is a disorder of the hypocretin system. One aspect of hypocretin activity is the direct excitation of cholinergic forebrain neurons, brainstem monoaminergic REM‐off neurons in the locus coeruleus and dorsal raphe nucleus, and histaminergic tuberomammillary nucleus, which together suppress slow‐wave sleep. The hypocretins also modulate the activity of cholinergic REM‐on neurons in the brainstem, which gate REM entry.

show abstract

Orexins/hypocretins excite basal forebrain cholinergic neurones

Cited by 285 publications

References 28 publications

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

The Dual Hypocretin Receptor Antagonist Almorexant is Permissive for Activation of Wake-Promoting Systems

Hypocretin/Orexin Innervation and Excitation of Identified Septohippocampal Cholinergic Neurons

Hypocretin/Orexin System

Contact Info

Product

Resources

About