Voltammetric detection of nitric oxide (NO) in the rat brain: its variations throughout the sleep-wake cycle

doi:10.1016/S0304-3940(97)00247-4

Neuroscience Letters

Volume 226, Issue 2, 25 April 1997, Pages 131-135

https://doi.org/10.1016/S0304-3940(97)00247-4 Get rights and content

Abstract

A sensor allowing the specific detection of nitric oxide (NO) is reported. Together with differential pulsed voltammetry, it allows the detection of a 650 mV signal either in NO solutions or in the rat frontal cortex. The intraperitoneal (i.p.) administration of a NO donor (S-nitrosoglutathione, 20 mg/kg i.p.) increases the signal height (+30%) while that of a nitric oxide synthase (NOS) inhibitor like l-nitro-arginine-p-nitro-anilide (100 mg/kg i.p.), produces its complete disappearance in the cortex of anesthetized rats. These results suggest that the 650 mV signal might be NO-dependent. Some other NOS inhibitors have been found either inefficient (l-nitro-arginine-methyl-ester) or partially efficient (7-nitro-indazole) on the signal height. In freely moving rats, also equipped with polygraphic electrodes, the signal measured in the frontal cortex exhibits the highest height during waking. It decreases during slow-wave sleep (−6%) and paradoxical sleep (−9%).

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Acknowledgements

This work was supported by INSERM-U52, CNRS-ERS5645 and SYNTHELABO (Donation Veille-Sommeil). We also thank C. Limoge for improving the English text.

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Nitric oxide (NO) has been implicated in the regulation of sleep. The perifornical-lateral hypothalamic area (PF-LHA) is a key wake-promoting region and contains neurons that are active during behavioral or cortical activation. Recently, we found higher levels of NO metabolites (NO_x), an indirect measure of NO levels, in the PF-LHA during prolonged waking (SD). However, NO is highly reactive and diffuses rapidly and the NO_x assay is not sensitive enough to detect rapid-changes in NO levels across spontaneous sleep-waking states. We used a novel Nafion®-modified Platinum (NF-PT) electrode for real-time detection of NO levels in the PF-LHA across sleep–wake cycles, dark–light phases, and during SD. Sprague–Dawley male rats were surgically prepared for chronic sleep–wake recording and implantation of NF-PT electrode into the PF-LHA. Electroencephalogram (EEG), electromyogram (EMG), and electrochemical current generated by NF-PT electrode were continuously acquired for 5–7 days including one day with 3 h of SD. In the PF-LHA, NO levels exhibited a waking > rapid eye movement (REM) > non-rapid eye movement (nonREM) sleep pattern (0.56 ± 0.03 μM > 0.47 ± 0.02 μM > 0.42 ± 0.02 μM; p < 0.01). NO levels were also higher during the dark- as compared to the light-phase (0.53 ± 0.03 μM vs. 0.44 ± 0.02 μM; p < 0.01). NO levels increased during 3 h of SD as compared to undisturbed control (0.58 ± 0.04 μM vs. 0.47 ± 0.01 μM; p < 0.05). The findings indicate that in the PF-LHA, NO is produced during behavioral or cortical activation. Since elevated levels of NO inhibits most of the PF-LHA neurons that are active during cortical activation, these findings support a hypothesis that NO produced in conjunction with the activation of PF-LHA neurons during waking/SD, inhibits the same neuronal population to promote sleep.
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The magnitude of this release, compared to that of the waking state (W), increases during SWS and is maximal during REM sleep59 (Fig. 3A). In the cortex, the level of the NO release is greater during W than in the course of SWS or REM sleep59,60 (Fig. 3A). While the functionality of the NO release observed in the nRD (likely a somatodendritic release) remains to be thoroughly analyzed, it may contribute to reduce the firing rate of serotoninergic neurons by way of a NO-induced release of glutamate which significantly contributes to the modulation of serotonin (5-HT) by kainate receptors.61
Nitric oxide (NO) production involves four different NO-synthases (NOSs) that are either constitutive (neuronal, nNOS; endothelial, eNOS; mitochondrial, mNOS) or inducible (iNOS) in nature. Three main processes regulate NO/NOSs output, i.e., the l-arginine/arginase substrate-competing system, the l-citrulline/arginosuccinate-recycling system and the asymmetric dimethyl-/monomethyl-l-arginine-inhibiting system. In adult animals, nNOS exhibits a dense innervation intermingled with pontine sleep structures. It is well established that the NO/nNOS production makes a key contribution to daily homeostatic sleep (slow-wave sleep, SWS; rapid eye movement sleep, REM sleep). In the basal hypothalamus, the NO/nNOS production further contributes to the REM sleep rebound that takes place after a sleep deprivation (SD). This production may also contribute to the sleep rebound that is associated with an immobilization stress (IS). In adult animals, throughout the SD time-course, an additional NO/iNOS production takes place in neurons. Such production mediates a transitory SD-related SWS rebound. A transitory NO/iNOS production is also part of the immune system. Such a production contributes to the SWS increase that accompanies inflammatory events and is ensured by microglial cells and astrocytes. Finally, with aging, the iNOS expression becomes permanent and the corresponding NO/iNOS production is important to ensure an adequate maintenance of REM sleep and, to a lesser extent, SWS. Despite such maintenance, aged animals, however, are not able to elicit a sleep rebound to deal with the challenge of SD or IS. Sleep regulatory processes in adult animals thus become impaired with age. Reduced iNOS expression during aging may contribute to accelerated senescence, as observed in senescence-accelerated mice (SAMP-8 mice).
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The perifornical-lateral hypothalamic area (PF-LHA) is a major wake-promoting structure. It predominantly contains neurons that are active during behavioral and cortical activation. PF-LHA stimulation produces arousal and PF-LHA lesions produce somnolence. Nitric oxide (NO) is a gaseous neurotransmitter that has been implicated in the regulation of multiple pathological and physiological processes including the regulation of sleep. NO levels are higher in the cortex and in the basal forebrain (BF) during arousal. In this study we determined whether NO levels increase in the PF-LHA during prolonged arousal and whether increased NO modulates the discharge activity of PF-LHA neurons. Experiments were conducted during lights-on phase between 8.00 and 20.00 h (lights-on at 8.00 h). First, we quantified levels of NO metabolites, NO₂⁻ and NO₃⁻ (collectively called NOx⁻) in the microdialysis dialysates collected from the PF-LHA during baseline (undisturbed rats), 6 h of sleep deprivation (SD), and recovery after SD. We further determined the effects of a NO donor, NOC-18, on the discharge activity of PF-LHA neurons in urethane-anesthetized rats. Overall, SD significantly affected NOx⁻ production in the PF-LHA (one way repeated measures ANOVA, F=7.827, P=0.004). The levels of NOx⁻ increased progressively in animals that were subjected to prolonged arousal as compared to the undisturbed predominantly sleeping animals and decreased during the recovery period. Local application of NOC-18 significantly suppressed the discharge of PF-LHA neurons including a majority of stimulus-on neurons or neurons exhibiting activation during electroencephalogram (EEG) desynchronization. The findings of this study suggest that in the PF-LHA, NO production is elevated during prolonged waking and that NO exerts predominantly inhibitory effects on PF-LHA neurons, especially on those neurons that are active during cortical activation. These findings are consistent with a hypothesis that NO in the PF-LHA plays a role in sleep regulation by inhibiting its neurons.

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Voltammetric detection of nitric oxide (NO) in the rat brain: its variations throughout the sleep-wake cycle

Abstract

Section snippets

Acknowledgements

Neurosci. Lett.

Eur. J. Pharmacol.

Neurosci. Lett.

Brain Res.

Brain Res. Bull.

J. Electroanal. Chem.

J. Neurosci. Methods

Mol. Brain Res.

Neurosci. Lett.

Localization of nitric oxide synthase indicating a neural role for nitric oxide

Nature