Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain

Vazquez-DeRose, Jacqueline; Schwartz, Michael D.; Nguyen, Alexander T.; Warrier, Deepti R; Gulati, Srishti; Th, Mathew; Neylan, Thomas C.; Kilduff, Thomas S.

doi:10.1007/s00429-014-0946-y

Cited by 22 publications

(18 citation statements)

References 76 publications

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“…Another clue as to the mechanisms underlying how Hcrt antagonists promote sleep comes from our recent study, demonstrating that ALM increases adenosine (ADO) levels in both the BF and cortex (Vazquez-DeRose et al, 2014), and that some of its sleep-promoting effects are dependent on the intact functionality of BF cholinergic neurons. Interestingly, microinjection of ALM directly into the BF both promoted sleep and increased ADO concentrations in the cortex, further supporting a role for the BF as a component of the circuitry underlying ALM's sleep-promoting effects.…”

Section: Discussionmentioning

confidence: 99%

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

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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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.

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Section: Discussionmentioning

confidence: 99%

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

Parks

Warrier

Dittrich

et al. 2015

Neuropsychopharmacol

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“…163-167 Hcrt receptor antagonists promote sleep when administered systemically or directly into the brain. 168-171 Indeed, newly-developed dual Hcrt receptor antagonists exhibit promise for the effective pharmacological promotion of sleep without adverse side effects such as cognitive performance deficits and dependence that are common to many sleep medications. 172, 173 …”

Section: The Hypocretin/orexin Systemmentioning

confidence: 99%

The Neurobiology of Sleep and Wakefulness

Schwartz

Kilduff

2015

Psychiatric Clinics of North America

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157

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SYNOPSIS Since the discovery of Rapid Eye Movement (REM) sleep in the late 1950s, identification of the neural circuitry underlying wakefulness, sleep onset and the alternation between REM and non-REM (NREM) sleep has been an active area of investigation. Synchronization and desynchronization of cortical activity as detected in the electroencephalogram (EEG) is due to a corticothalamocortical loop, intrinsic cortical oscillators, monoaminergic and cholinergic afferent input to the thalamus, and the basal forebrain cholinergic input directly to the cortex. The monoaminergic and cholinergic systems are largely wake-promoting; the brainstem cholinergic nuclei are also involved in REM sleep regulation. These wake-promoting systems receive excitatory input from the hypothalamic hypocretin/orexin system. Sleep-promoting nuclei are GABAergic in nature and found in the preoptic area, brainstem and lateral hypothalamus. Although the pons is critical for the expression of REM sleep, recent research has suggested that melanin-concentrating hormone/GABAergic cells in the lateral hypothalamus "gate" REM sleep. The temporal distribution of sleep and wakefulness is due to interaction between the circadian system and the sleep homeostatic system. Although the hypothalamic suprachiasmatic nuclei contain the circadian pacemaker, the neural circuitry underlying the sleep homeostat is less clear. Prolonged wakefulness results in the accumulation of extracellular adenosine, possibly from glial sources, which is an important feedback molecule for the sleep homeostatic system. Cortical neuronal nitric oxide (nNOS) neurons may also play a role in propagating slow waves through the cortex in NREM sleep. Several neuropeptides and other neurochemicals likely play important roles in sleep/wake control. Although the control of sleep and wakefulness seemingly involves multiple redundant systems, each of these systems provides a vulnerability that can result in sleep/wake dysfunction that may predispose to physical and/or neuropsychiatric disorders.

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“…; Vazquez‐DeRose et al . ). The first report of adenosine being analysed by microdialysis appeared in 1982 (Zetterstrom et al .…”

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confidence: 97%

Intracerebral microdialysis of adenosine and adenosine monophosphate – a systematic review and meta‐regression analysis of baseline concentrations

Mierden

Savelyev²,

IntHout

et al. 2018

Journal of Neurochemistry

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Microdialysis is a method to study the extracellular space in vivo, based on the principle of diffusion. It can be used to measure various small molecules including the neuroregulator adenosine. Baseline levels of the compounds measured with microdialysis vary over studies. We systematically reviewed the literature to investigate the full range of reported baseline concentrations of adenosine and adenosine monophosphate in microdialysates. We performed a meta‐regression analysis to study the influence of flow rate, probe membrane surface area, species, brain area and anaesthesia versus freely behaving, on the adenosine concentration. Baseline adenosine concentrations in microdialysates ranged from 0.8 to 2100 nM. There was limited evidence on baseline adenosine monophosphate concentrations in microdialysates. Across studies, we found effects of flow rate and anaesthesia versus freely behaving on dialysate adenosine concentrations (p ≤ 0.001), but not of probe membrane surface, species, or brain area (p ≥ 0.14). With increasing flow rate, adenosine concentrations decreased. With anaesthesia, adenosine concentrations increased. The effect of other predictor variables on baseline adenosine concentrations, for example, post‐surgical recovery time, could not be analysed because of a lack of reported data. This study shows that meta‐regression can be used as an alternative to new animal experiments to answer research questions in the field of neurochemistry. However, current levels of reporting of primary studies are insufficient to reach the full potential of this approach; 63 out of 133 studies could not be included in the analysis because of insufficient reporting, and several potentially relevant factors had to be excluded from the analyses. The level of reporting of experimental detail needs to improve.

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Hypocretin/orexin antagonism enhances sleep-related adenosine and GABA neurotransmission in rat basal forebrain

Cited by 22 publications

References 76 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

The Neurobiology of Sleep and Wakefulness

Intracerebral microdialysis of adenosine and adenosine monophosphate – a systematic review and meta‐regression analysis of baseline concentrations

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