Pontine nitric oxide modulates acetylcholine release, rapid eye movement sleep generation, and respiratory rate

Department of Anesthesia, Pennsylvania State University College of Medicine, Hershey 17033, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/1997; 17(2):774-85.
Source: PubMed


Pontine cholinergic neurotransmission is known to play a key role in the regulation of rapid eye movement (REM) sleep and to contribute to state-dependent respiratory depression. Nitric oxide (NO) has been shown to alter the release of acetylcholine (ACh) in a number of brain regions, and previous studies indicate that NO may participate in the modulation of sleep/wake states. The present investigation tested the hypothesis that inhibition of NO synthase (NOS) within the medial pontine reticular formation (mPRF) of the unanesthetized cat would decrease ACh release, inhibit REM sleep, and prevent cholinergically mediated respiratory depression. Local NOS inhibition by microdialysis delivery of N(G)-nitro-L-arginine (NLA) significantly reduced ACh release in the cholinergic cell body region of the pedunculopontine tegmental nucleus and in the cholinoceptive mPRF. A second series of experiments demonstrated that mPRF microinjection of NLA significantly reduced the amount of REM sleep and the REM sleep-like state caused by mPRF injection of the acetylcholinesterase inhibitor neostigmine. Duration but not frequency of REM sleep epochs was significantly decreased by mPRF NLA administration. Injection of NLA into the mPRF before neostigmine injection also blocked the ability of neostigmine to decrease respiratory rate during the REM sleep-like state. Taken together, these findings suggest that mPRF NO contributes to the modulation of ACh release, REM sleep, and breathing.

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Available from: Ralph Lydic, Dec 23, 2015
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    • "A promising candidate is the sublaterodorsal nucleus (SLD), which contains glutamatergic neurons that are crucial for the generation of atonia during REM sleep [54]. Acetylcholine is thought to participate in the activation of these descending atonia pathways as increases in glutamatergic input to SLD neurons occur during REM sleep when the levels of acetylcholine in the dorsal pons are highest [55]. LY354740 has been shown to inhibit the electrically-evoked endogenous acetylcholine release in brain slices [56] as well as the NMDA-evoked [3H]-choline release from synaptosomes and acetylcholine release in brain slices [57] . "
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    ABSTRACT: G-protein-coupled receptor (GPCR) agonists are known to induce both cellular adaptations resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment discontinuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, which processes have translational relevance for central activity and target engagement. Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate receptors (mGluR2/3) agonist LY354740 versus mGluR2 positive allosteric modulator (PAM) JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of LY354740 (1-10 mg/kg) and JNJ-42153605 (3-30 mg/kg). JNJ-42153605 showed high affinity, potency and selectivity at mGluR2. Binding site analyses and knowledge-based docking confirmed the specificity of JNJ-42153605 at the mGluR2 allosteric binding site. Acute LY354740 and JNJ-42153605 dose-dependently decreased rapid eye movement (REM) sleep time and prolonged its onset latency. Sub chronic effects of LY354740 on REM sleep measures disappeared from day 3 onwards, whereas those of JNJ-42153605 were maintained after repeated exposure. LY354740 attenuated REM sleep homeostatic recovery, while this was preserved after JNJ-42153605 administration. JNJ-42153605 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for impaired sleep quality during early stages of treatment. Abrupt cessation of JNJ-42153605 did not induce withdrawal phenomena and sleep disturbances, while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with JNJ-42153605 did not induce tolerance phenomena to its primary functional effects on sleep measures, nor adverse effects at withdrawal, while it promoted homeostatic recovery sleep. From the translational perspective, the present rodent findings suggest that mGluR2 positive allosteric modulation has therapeutic potential based on its superior long term efficacy over agonists in psychiatric disorders, particularly of those commonly occurring with REM sleep overdrive.
    Full-text · Article · Dec 2015 · PLoS ONE
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    • "Consistent with the preceding data, the microinjection of cholinergic, muscarinic agonists or anticholinesterases into the region of the AS- Generator elicits, with a short latency, both individual elements of AS (e.g., atonia, PGO waves, rapid eye movements, etc.) as well as the complete state of AS, with all of its attendant physiological patterns of activity (Baghdoyan et al., 1989; George et al., 1964; Shiromani et al., 1992; Vanni-Mercier et al., 1989; Yamamoto et al., 1990a, 1990b; Yamuy et al., 1993). In further support of the concept that AS is initiated by the activation of cholinergic mechanisms, studies that employ microdialysis techniques have demonstrated that acetylcholine release is enhanced during pharmacologically-induced as well as naturally-occurring AS (Kodama et al., 1990; Leonard and Lydic, 1997; Lydic et al., 1991). Finally, there is an increase in the discharge of a majority of NPO neurons during AS (McCarley and Hobson, 1971; McCarley et al., 1995; Sakai, 1988). "
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    ABSTRACT: There is a consensus that active sleep (AS; i.e., REM sleep) is produced by cholinergic projections from the pedunculopontine tegmental nuclei (PPT) that activate AS-on neurons in the nucleus pontis oralis (NPO) that are components of the AS-Generator. However, there is a growing body of evidence indicating that other sites, such as the amygdala, also participate in the control of AS by inducing the discharge of AS-Generator neurons. In this regard, we recently reported that there are direct, excitatory (glutamatergic) projections from the central nucleus of the amygdala (CNA) to presumptive AS-Generator neurons in the NPO. We therefore hypothesized that the CNA and the PPT act alone, as well as in concert, to promote AS. To test this hypothesis, the effects of stimulation of the CNA and the PPT on the activity of NPO neurons, recorded intracellularly, were examined in urethane-anesthetized rats. Stimulation of either the CNA or the PPT evoked short-latency excitatory postsynaptic potentials (EPSPs) in the same neurons within the NPO. The amplitude of PPT-evoked EPSPs that were recorded from NPO neurons increased by 20.1 to 58.6% when stimulation of the PPT was preceded by stimulation of the CNA at an interval of 0 to 12ms: maximal potentiation occurred at an interval of 4 to 6ms. Concurrent subthreshold stimulation of the CNA and the PPT resulted in the discharge of NPO neurons. NPO neurons that were activated following CNA and/or PPT stimulation were identified morphologically and found to be multipolar with diameters>20μm; similar neurons in the same NPO site have been previously identified as AS-Generator neurons. The present data demonstrate the presence of converging excitatory synaptic inputs from the CNA and the PPT that are capable of promoting the discharge of AS-Generator neurons in the NPO. Therefore, we suggest that the occurrence of AS depends upon interactions between cholinergic projections from the PPT and glutamatergic projections from the CNA as well as inputs from other sites that project to AS-Generator neurons.
    Full-text · Article · Aug 2012 · Experimental Neurology
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    • "The ACh/GABA ratio (Fig. 4) provides an innovative proportionality index of neurochemical excitation and inhibition. ACh release in the pontine reticular formation increases significantly during REM sleep relative to wakefulness and NREM sleep (Leonard and Lydic, 1997). Furthermore, causing an increase in ACh levels in the pontine reticular formation causes an increase in REM sleep (Baghdoyan et al., 1984; Lydic and Baghdoyan, 1993; Thakkar et al., 1996). "
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    ABSTRACT: Studies using drugs that increase or decrease GABAergic transmission suggest that GABA in the pontine reticular formation (PRF) promotes wakefulness and inhibits rapid eye movement (REM) sleep. Cholinergic transmission in the PRF promotes REM sleep, and levels of endogenous acetylcholine (ACh) in the PRF are significantly greater during REM sleep than during wakefulness or non-REM (NREM) sleep. No previous studies have determined whether levels of endogenous GABA in the PRF vary as a function of sleep and wakefulness. This study tested the hypothesis that GABA levels in cat PRF are greatest during wakefulness and lowest during REM sleep. Extracellular GABA levels were measured during wakefulness, NREM sleep, REM sleep, and the REM sleep-like state (REM(Neo)) caused by microinjecting neostigmine into the PRF. GABA levels varied significantly as a function of sleep and wakefulness, and decreased significantly below waking levels during REM sleep (-42%) and REM(Neo) (-63%). The decrease in GABA levels during NREM sleep (22% below waking levels) was not statistically significant. Compared with NREM sleep, GABA levels decreased significantly during REM sleep (-27%) and REM(Neo) (-52%). Comparisons of REM sleep and REM(Neo) revealed no differences in GABA levels or cortical EEG power. GABA levels did not vary significantly as a function of dialysis site within the PRF. The inverse relationship between changes in PRF levels of GABA and ACh during REM sleep indicates that low GABAergic tone combined with high cholinergic tone in the PRF contributes to the generation of REM sleep.
    Full-text · Article · Feb 2011 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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