Role of adenosine A1 receptor in the perifornical–lateral hypothalamic area in sleep–wake regulation in rats

Alam, Md. Noor; Kumar, Sunil; Rai, Seema; Methippara, Melvi; Szymusiak, Ronald; McGinty, Dennis

doi:10.1016/j.brainres.2009.09.066

Cited by 32 publications

(28 citation statements)

References 52 publications

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“…1A) [22] , consistent with previous reports [17] . Based on the location of microinjection sites, the areas of perfused drugs were confirmed to include the orexin neurons in the lateral hypothalamus.…”

Section: Identifi Cation Of the Site Of Drug Deliverysupporting

confidence: 83%

“…In addition to the key role in promoting wakefulness, abundant evidence has demonstrated that orexin neurons are a potential target in the sleep-producing effect of endogenous adenosine, in which blockade of adenosine A1 receptors in the lateral hypothalamus induces a signifi cant increase in wakefulness with a concomitant reduction in sleep [17,19] . Consistently, we found that the exogenous application of adenosine into the lateral hypothalamus enhanced sleep.…”

Section: Discussionmentioning

confidence: 99%

“…Recent behavioral experiments with adenosine antagonists in vivo have suggested that orexin neurons are another important target involved in the hypnotic action of adenosine [16,17,19,27] . In this study, we further explored the role of exogenous adenosine in the regulation of sleep and wakefulness in the lateral hypothalamus.…”

Section: Sleep and Wakefulnessmentioning

confidence: 99%

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Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

et al. 2014

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Orexin neurons within the lateral hypothalamus play a crucial role in the promotion and maintenance of arousal. Studies have strongly suggested that orexin neurons are an important target in endogenous adenosine-regulated sleep homeostasis. Orexin A induces a robust increase in the firing activity of orexin neurons, while adenosine has an inhibitory effect. Whether the excitatory action of orexins in the lateral hypothalamus actually promotes wakefulness and reverses the sleep-producing effect of adenosine in vivo is less clear. In this study, electroencephalographic and electromyographic recordings were used to investigate the effects of orexin A and adenosine on sleep and wakefulness in rats. We found that microinjection of orexin A into the lateral hypothalamus increased wakefulness with a concomitant reduction of sleep during the first 3 h of post-injection recording, and this was completely blocked by a selective antagonist for orexin receptor 1, SB 334867. The enhancement of wakefulness also occurred after application of the excitatory neurotransmitter glutamate in the fi rst 3 h post-injection. However, in the presence of the NMDA receptor antagonist APV, orexin A did not induce any change of sleep and wakefulness in the first 3 h. Further, exogenous application of adenosine into the lateral hypothalamus induced a marked increase of sleep in the fi rst 3-h post-injection. No signifi cant change in sleep and wakefulness was detected after adenosine application followed by orexin A administration into the same brain area. These findings suggest that the sleep-promoting action of adenosine can be reversed by orexin A applied to the lateral hypothalamus, perhaps by exciting glutamatergic input to orexin neurons via the action of orexin receptor 1.

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Section: Identifi Cation Of the Site Of Drug Deliverysupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

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Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

et al. 2014

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“…CPA significantly suppressed the sleep-wake discharge activity of PF-LHA neurons. Doses of CPA (50μM) and CPDX (50μM) that suppressed and induced arousal, respectively, in our earlier study (Alam et al, 2009), significantly suppressed and increased Fos-IR in HCRT and non-HCRT neurons. These findings suggest that wake-promoting PF-LHA system is subject to increased endogenous adenosinergic inhibition and that adenosine acting via A 1 receptors, in part, inhibits HCRT neurons to promote sleep.…”

mentioning

confidence: 51%

A1 receptor mediated adenosinergic regulation of perifornical–lateral hypothalamic area neurons in freely behaving rats

et al. 2010

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The perifornical-lateral hypothalamic area (PF-LHA) plays a central role in the regulation of behavioral arousal. The PF-LHA contains several neuronal types including wake-active hypocretin (HCRT) neurons that have been implicated in the promotion and/or maintenance of behavioral arousal. Adenosine is an endogenous sleep factor and recent evidence suggests that activation and blockade of adenosine A1 receptors within the PF-LHA promote and suppress sleep, respectively. Although, an in vitro study indicates that adenosine inhibits HCRT neurons via A1 receptor, the in vivo effects of A1 receptor mediated adenosinergic transmission on PF-LHA neurons including HCRT neurons are not known. First, we determined the effects of N6-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, on the sleep-wake discharge activity of the PF-LHA neurons recorded via microwires placed adjacent to the microdialysis probe used for its delivery. Second, we determined the effects of CPA and that of an A1 receptor antagonist, 1,3-dipropyl-8-phenylxanthine (CPDX) into the PF-LHA on cFos-protein immunoreactivity (Fos-IR) in HCRT and non-HCRT neurons around the microdialysis probe used for their delivery. The effect of CPA was studied in rats that were kept awake during lights-off phase, whereas the effect of CPDX was examined in undisturbed rats during lights-on phase. CPA significantly suppressed the sleep-wake discharge activity of PF-LHA neurons. Doses of CPA (50μM) and CPDX (50μM) that suppressed and induced arousal, respectively, in our earlier study (Alam et al., 2009), significantly suppressed and increased Fos-IR in HCRT and non-HCRT neurons. These findings suggest that wake-promoting PF-LHA system is subject to increased endogenous adenosinergic inhibition and that adenosine acting via A1 receptors, in part, inhibits HCRT neurons to promote sleep.

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“…Adenosine and A 1 R agonists inhibit activity of the hypocretin/orexin neurons in this area via A 1 R which promotes sleep [67,68]. On the other hand, blockade of A 1 R in such neurons causes a pronounced increase in wakefulness [68,69]. Adenosine reduces the frequency of action potentials in hypocretin/orexin neurons by depressing excitatory synaptic transmission to these cells.…”

Section: Sleep-wake Regulationmentioning

confidence: 99%

Adenosine A1 Receptors in the Central Nervous System: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging

Paul¹,

Elsinga²,

Ishiwata³

et al. 2011

CMC

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Adenosine is a neuromodulator with several functions in the central nervous system (CNS), such as inhibition of neuronal activity in many signaling pathways. Most of the sedating, anxiolytic, seizure-inhibiting and protective actions of adenosine are mediated by adenosine A1 receptors (A1R) on the surface of neurons and glia. Positron Emission Tomography (PET) is a powerful in vivo imaging tool which can be applied to investigate the physiologic and pathologic roles of A1R in the human brain, and to elucidate the mechanism of action of therapeutic drugs targeting adenosine receptors, nucleoside transporters and adenosine-degrading enzymes. In this review article, we discuss (i) functions of adenosine and its receptors in cerebral metabolism; (ii) radioligands for A1R imaging: xanthine antagonists, non-xanthine antagonists, and agonists; (iii) roles of A1R in health and disease, viz. sleep-wake regulation, modulation of memory retention and retrieval, mediating the effects of alcohol consumption, protecting neurons during ischemia and reperfusion, suppression of seizures, modulating neuroinflammation and limiting brain damage in neurodegenerative disorders. The application of PET imaging could lead to novel insights in these areas. Finally (iv), we discuss the application of PET in pharmacodynamic studies and we examine therapeutic applications of adenosine kinase inhibitors, e.g. in the treatment of pain, inflammation, and epilepsy.

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Role of adenosine A1 receptor in the perifornical–lateral hypothalamic area in sleep–wake regulation in rats

Cited by 32 publications

References 52 publications

Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

Orexin A attenuates the sleep-promoting effect of adenosine in the lateral hypothalamus of rats

A1 receptor mediated adenosinergic regulation of perifornical–lateral hypothalamic area neurons in freely behaving rats

Adenosine A1 Receptors in the Central Nervous System: Their Functions in Health and Disease, and Possible Elucidation by PET Imaging

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