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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    ABSTRACT: Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K(+), AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state.
    PLoS ONE 01/2013; 8(1):e53814. DOI:10.1371/journal.pone.0053814 · 3.23 Impact Factor
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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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    ABSTRACT: Sleep, which is evolutionarily conserved across species, is a biological imperative that cannot be ignored or replaced. However, the percentage of habitually sleep-restricted adults has increased in recent decades. Extended work hours and commutes, shift work schedules, and television viewing are particularly potent social factors that influence sleep duration. Chronic partial sleep restriction, a product of these social expediencies, leads to the accumulation of sleep debt over time and consequently increases sleep propensity, decreases alertness, and impairs critical aspects of cognitive functioning. Significant interindividual variability in the neurobehavioral responses to sleep restriction exists-this variability is stable and phenotypic-suggesting a genetic basis. Identifying vulnerability to sleep loss is essential as many adults cannot accurately judge their level of impairment in response to sleep restriction. Indeed, the consequences of impaired performance and the lack of insight due to sleep loss can be catastrophic. In order to cope with the effects of social expediencies on biological imperatives, identification of biological (including genetic) and behavioral markers of sleep loss vulnerability as well as development of technological approaches for fatigue management are critical.
    Progress in brain research 08/2012; 199:377-98. DOI:10.1016/B978-0-444-59427-3.00021-6 · 2.83 Impact Factor
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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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    ABSTRACT: The basal forebrain (BF) is an important mediator of cortical arousal, which is innervated by all ascending arousal systems. During sleep deprivation (SD) a site-specific accumulation of sleep factors in the BF results in increased sleep pressure (Kalinchuk et al., 2006; Porkka-Heiskanen et al., 1997; Porkka-Heiskanen et al., 2000). However, animals are able to stay awake and even increase their neuronal activity in the BF and cortex during SD, suggesting increased activity of the ascending arousal systems to counteract the effect of sleep pressure. This study used in vivo microdialysis to measure the effect of a 6h SD, by "gentle handling" in freely moving rats, on the extracellular levels of serotonin and dopamine metabolites (5-HIAA, and DOPAC and HVA respectively) in the BF. Additionally, because glucocorticoids can interact with monoaminergic neurotransmission, and SD could be stressful, corticosterone levels were measured. We found an increase in extracellular serotonin and dopamine metabolite levels (n=8, p≤0.05). No interaction between corticosterone and the monoaminergic systems was apparent. Extracellular corticosterone levels showed no increase during the first 3h of SD, and the subsequent increase (n=8, p≤0.05) did not result in values exceeding the normal diurnal maximum, indicating that no substantial stress was induced. The results demonstrate that SD increases extracellular dopamine and serotonin metabolites in the BF, suggesting increased activity of the ascending arousal systems. It remains to be investigated what the specific roles of the dopaminergic and serotonergic ascending arousal systems are in BF-mediated cortical arousal.
    Brain research 07/2011; 1399:40-8. DOI:10.1016/j.brainres.2011.05.008 · 2.84 Impact Factor
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