Role of adenosine A(1) receptor in the perifornical-lateral hypothalamic area in sleep-wake regulation in rats

Research Service (151A3), Veterans Affairs Greater Los Angeles Healthcare System, 16111 Plummer Street, Sepulveda, CA 91343, USA.
Brain research (Impact Factor: 2.84). 09/2009; 1304:96-104. DOI: 10.1016/j.brainres.2009.09.066
Source: PubMed


The perifornical-lateral hypothalamic area (PF-LHA) has been implicated in the regulation of arousal. The PF-LHA contains wake-active neurons that are quiescent during non-REM sleep and in the case of neurons expressing the peptide hypocretin (HCRT), quiescent during both non-REM and REM sleep. Adenosine is an endogenous sleep factor and recent evidence suggests that adenosine via A(1) receptors may act on PF-LHA neurons to promote sleep. We examined the effects of bilateral activation as well as blockade of A(1) receptors in the PF-LHA on sleep-wakefulness in freely behaving rats. The sleep-wake profiles of male Wistar rats were recorded during reverse microdialysis perfusion of artificial cerebrospinal fluid (aCSF) and two doses of adenosine A(1) receptor antagonist, 1,3-dipropyl-8-phenylxanthine (CPDX; 5 microM and 50 microM) or A(1) receptor agonist, N(6)-cyclopentyladenosine (CPA; 5 microM and 50 microM) into the PF-LHA for 2 h followed by 4 h of aCSF perfusion. CPDX perfused into the PF-LHA during lights-on phase produced arousal (F=7.035, p<0.001) and concomitantly decreased both non-REM (F=7.295, p<0.001) and REM sleep (F=3.456, p<0.004). In contrast, CPA perfused into the PF-LHA during lights-off phase significantly suppressed arousal (F=7.891, p<0.001) and increased non-REM (F=8.18, p <0.001) and REM sleep (F=30.036, p<0.001). These results suggest that PF-LHA is one of the sites where adenosine, acting via A(1) receptors, inhibits PF-LHA neurons to promote sleep.

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    • "AdorA1 KO and AdorA2a KO mice both exhibit similar spontaneous REMS and REMS responses to sleep loss as their WT controls further suggesting that adenosine has little role in regulating REMS (Huang et al., 2005; Stenberg et al., 2003). Nevertheless, AdorA1 agonists can suppress or enhance REMS (Benington et al., 1995; Alam et al., 2009), while AdorA1 antagonists suppress REMS suggesting adenosine receptors have an influence on REMS (Thakkar et al., 2008; Alam et al., 2009). Further, AdorA2a agonists and AdorA2a antagonists have the capacity to alter REMS (Coleman et al., 2006; Satoh et al., 1996, 2006). "
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    ABSTRACT: Adenosine and extracellular adenosine triphosphate (ATP) have multiple physiological central nervous system actions including regulation of cerebral blood flow, inflammation and sleep. However, their exact sleep regulatory mechanisms remain unknown. Extracellular ATP and adenosine diphosphate are converted to adenosine monophosphate (AMP) by the enzyme ectonucleoside triphosphate diphosphohydrolase 1, also known as CD39, and extracellular AMP is in turn converted to adenosine by the 5'-ectonuleotidase enzyme CD73. We investigated the role of CD73 in sleep regulation. Duration of spontaneous non-rapid eye movement sleep (NREMS) was greater in CD73-knockout (KO) mice than in C57BL/6 controls whether determined in our laboratory or by others. After sleep deprivation (SD), NREMS was enhanced in controls but not CD73-KO mice. Interleukin-1 beta (IL1β) enhanced NREMS in both strains, indicating that the CD73-KO mice were capable of sleep responses. Electroencephalographic power spectra during NREMS in the 1.0-2.5 Hz frequency range was significantly enhanced after SD in both CD73-KO and WT mice; the increases were significantly greater in the WT mice than in the CD73-KO mice. Rapid eye movement sleep did not differ between strains in any of the experimental conditions. With the exception of CD73 mRNA, the effects of SD on various adenosine-related mRNAs were small and similar in the two strains. These data suggest that sleep is regulated, in part, by extracellular adenosine derived from the actions of CD73.
    European Journal of Neuroscience 04/2012; 35(11):1789-98. DOI:10.1111/j.1460-9568.2012.08112.x · 3.18 Impact Factor
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    • "Based on these findings, we can speculate that endogenous adenosine, accumulated as increased activity of hypocretin neurons and glutamatergic transmission in wakefulness, would exert an inhibitory effect on these neurons and promote sleep eventually, while in sleep the extracellular release of adenosine will be decreased due to the large of inhibitory afferents and lacking of the excitatory transmission, which rarely affect the inhibitory action of GABAergic transmission in hypocretin neurons. This speculation is in line with the changes of hypocretin neurons firing fast during waking and ceasing in sleep (Alam et al., 2002), as well as the net inhibitory effect and sleep-promoting action of endogenous adenosine on hypocretin neurons observed in vivo behavioral study (Thakkar et al., 2008; Alam et al., 2009). On the other hand, the limit of GABAergic activity by adenosine would prevent too strong an inhibition of hypocretin neurons and maintain a minimal level of hypocretin peptide–released activity, which would eventually promote wakefulness. "
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    ABSTRACT: Hypocretin neurons in the lateral hypothalamus, a new wakefulness-promoting center, have been recently regarded as an important target involved in endogenous adenosine-regulating sleep homeostasis. The GABAergic synaptic transmissions are the main inhibitory afferents to hypocretin neurons, which play an important role in the regulation of excitability of these neurons. The inhibitory effect of adenosine, a homeostatic sleep-promoting factor, on the excitatory glutamatergic synaptic transmissions in hypocretin neurons has been well documented, whether adenosine also modulates these inhibitory GABAergic synaptic transmissions in these neurons has not been investigated. In this study, the effect of adenosine on inhibitory postsynaptic currents (IPSCs) in hypocretin neurons was examined by using perforated patch-clamp recordings in the acute hypothalamic slices. The findings demonstrated that adenosine suppressed the amplitude of evoked IPSCs in a dose-dependent manner, which was completely abolished by 8-cyclopentyltheophylline (CPT), a selective antagonist of adenosine A1 receptor but not adenosine A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl) xanthine. A presynaptic origin was suggested as following: adenosine increased paired-pulse ratio as well as reduced GABAergic miniature IPSC frequency without affecting the miniature IPSC amplitude. Further findings demonstrated that when the frequency of electrical stimulation was raised to 10 Hz, but not 1 Hz, a time-dependent depression of evoked IPSC amplitude was detected in hypocretin neurons, which could be partially blocked by CPT. However, under a higher frequency at 100 Hz stimulation, CPT had no action on the depressed GABAergic synaptic transmission induced by such tetanic stimulation in these hypocretin neurons. These results suggest that endogenous adenosine generated under certain stronger activities of synaptic transmissions exerts an inhibitory effect on GABAergic synaptic transmission in hypocretin neurons by activation of presynaptic adenosine A1 receptors, which may finely regulate the excitability of these neurons as well as eventually modulate the sleep-wakefulness.
    Neuroscience 11/2011; 201:46-56. DOI:10.1016/j.neuroscience.2011.11.019 · 3.36 Impact Factor
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    • "The A 1 receptor agonist concentration that suppressed waking and induced nonREM/REM sleep after its perfusion into the PF-LHA in our earlier study (Alam et al., 2009), suppressed Fos-IR in HCRT and other PF-LHA neurons in this study. In contrast, the A 1 receptor antagonist concentration that produced arousal and suppressed nonREM/REM sleep in our earlier study increased Fos-IR in HCRT and other PF-LHA neurons. "
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    ABSTRACT: 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 A(1) receptors within the PF-LHA promote and suppress sleep, respectively. Although, an in vitro study indicates that adenosine inhibits HCRT neurons via A(1) receptor, the in vivo effects of A(1) receptor mediated adenosinergic transmission on PF-LHA neurons including HCRT neurons are not known. First, we determined the effects of N(6)-cyclopentyladenosine (CPA), an adenosine A(1) 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 A(1) 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 on Fos-IR 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 (50 muM) and CPDX (50 muM) that suppressed and induced arousal, respectively, in our earlier study [Alam MN, Kumar S, Rai S, Methippara M, Szymusiak R, McGinty D (2009) Brain Res 1304:96-104], 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.
    Neuroscience 04/2010; 167(1):40-8. DOI:10.1016/j.neuroscience.2010.01.044 · 3.36 Impact Factor
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