Nitric oxide production in the basal forebrain is required for recovery sleep

Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Journal of Neurochemistry (Impact Factor: 4.28). 11/2006; 99(2):483-98. DOI: 10.1111/j.1471-4159.2006.04077.x
Source: PubMed


Sleep homeostasis is the process by which recovery sleep is generated by prolonged wakefulness. The molecular mechanisms underlying this important phenomenon are poorly understood. Here, we assessed the role of the intercellular gaseous signaling agent NO in sleep homeostasis. We measured the concentration of nitrite and nitrate, indicative of NO production, in the basal forebrain (BF) of rats during sleep deprivation (SD), and found the level increased by 100 +/- 51%. To test whether an increase in NO production might play a causal role in recovery sleep, we administered compounds into the BF that increase or decrease concentrations of NO. Infusion of either a NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, or a NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME), completely abolished non-rapid eye movement (NREM) recovery sleep. Infusion of a NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2diolate (DETA/NO), produced an increase in NREM that closely resembled NREM recovery after prolonged wakefulness. The effects of inhibition of NO synthesis and the pharmacological induction of sleep were effective only in the BF area. Indicators of energy metabolism, adenosine, lactate and pyruvate increased during prolonged wakefulness and DETA/NO infusion, whereas L-NAME infusion during SD prevented the increases. We conclude that an increase in NO production in the BF is a causal event in the induction of recovery sleep.

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Available from: Paul A Rosenberg, Dec 26, 2014
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    • "In vivo, BFB extracellular adenosine levels in rats are observed to increase with increased wakefulness and decrease with increased sleep, and increase considerably more during sleep deprivation. This is consistent with evidence of adenosine release due to neuronal activity [17], [37]–[39], as BFB cellular activity increases during periods of wakefulness and is considerably lower during NREM sleep according to juxtacellular recordings [40], [41] and c-fos activity [42]. Whole cell patch clamp recordings were made from BFB neurons whilst extracellular adenosine and inosine concentrations were concurrently recorded with biosensors. "
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    • "Researchers have found that slow waves, low-frequency EEG, likely represent a measure of sleep intensity—extended waking leads to increases in slow wave energy (SWE) during the subsequent recovery night and the extent of this SWE increase is a function of prior wake duration (Åkerstedt et al., 2009; Brunner et al., 1990). In addition to SWE, other biological markers of sleep homeostasis have been identified including extracellular adenosine, central nitrous oxide levels, and salivary amylase; levels of these markers increase with prolonged sleep– wakefulness and thus may reflect an increased sleep drive (Kalinchuk et al., 2006; Porkka- Heiskanen and Kalinchuk, 2011; Scharf et al., 2008; Seugnet et al., 2006). The homeostatic process of sleep–wake regulation interacts with but is independent from circadian control (Dijk et al., 1989). "
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    • "during SD suppresses rebound NREM sleep during recovery sleep (Sallanon et al., 1983). Our results show a slow and gradual build-up of serotonin turnover in the BF, which has a similar time scale as the adenosine (AD) build-up during SD (Kalinchuk et al., 2006; Porkka-Heiskanen et al., 1997). AD acts in the BF by inhibiting cholinergic neurons. "
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