A method of nodose ganglia injection in Sprague-Dawley rat.

Afferent signaling via the vagus nerve transmits important general visceral information to the central nervous system from many diverse receptors located in the organs of the abdomen and thorax. The vagus nerve communicates information from stimuli such as heart rate, blood pressure, bronchopulmonary irritation, and gastrointestinal distension to the nucleus of solitary tract of the medulla. The cell bodies of the vagus nerve are located in the nodose and petrosal ganglia, of which the majority are located in the former.

Acute exacerbation of sleep apnea by hyperoxia impairs cognitive flexibility in Brown-Norway rats.

Study Objectives: To determine whether learning deficits occur during acute exacerbation of spontaneous sleep related breathing disorder (SRBD) in rats with high (Brown Norway; BN) and low (Zucker Lean; ZL) apnea propensity.

Design: Spatial acquisition (3 days) and reversal learning (3 days) in the Morris water maze (MWM) with polysomnography (12:00-08:00): (1) with acute SRBD exacerbation (by 20-h hyperoxia immediately preceding reversal learning) or (2) without SRBD exacerbation (room air throughout).

Setting: Randomized, placebo-controlled, repeated-measures design.

Brown Norway and Zucker Lean rats demonstrate circadian variation in ventilation and sleep apnea.

Study Objectives: Circadian rhythms influence many biological systems, but there is limited information about circadian and diurnal variation in sleep related breathing disorder. We examined circadian and diurnal patterns in sleep apnea and ventilatory patterns in two rat strains, one with high sleep apnea propensity (Brown Norway [BN]) and the other with low sleep apnea propensity (Zucker Lean [ZL]).

Design/setting: Chronically instrumented rats were randomized to breathe room air (control) or 100% oxygen (hyperoxia), and we performed 20-h polysomnography beginning at Zeitgeber time 4 (ZT 4; ZT 0 = lights on, ZT12 = lights off).

Intranodose ganglion injections of dronabinol attenuate serotonin-induced apnea in Sprague-Dawley rat.

Obstructive sleep apnea represents a significant public health concern. Afferent vagal activation is implicated in increased apnea susceptibility by reducing upper airway muscle tone via activation of serotonin receptors in the nodose ganglia. Previous investigations demonstrated that systemically administered cannabinoids can be used therapeutically to decrease the apnea/hypopnea index in rats and in humans.

Proof of concept trial of dronabinol in obstructive sleep apnea.

Study Objective: Animal data suggest that Δ(9)-TetraHydroCannabinol (Δ(9)THC) stabilizes autonomic output during sleep, reduces spontaneous sleep-disordered breathing, and blocks serotonin-induced exacerbation of sleep apnea. On this basis, we examined the safety, tolerability, and efficacy of dronabinol (Δ(9)THC), an exogenous Cannabinoid type 1 and type 2 (CB1 and CB2) receptor agonist in patients with Obstructive Sleep Apnea (OSA).

Design And Setting: Proof of concept; single-center dose-escalation study of dronabinol.

[Humoral sleep theories].

The common feature that characterized humoral theories of sleep is the production and accumulation of certain substances, usually end-products of metabolism, either in the tissues, in general, or in certain organs, such as the brain. When a definite concentration of such substances has been reached, the activity of the brain is depressed either directly, or through indirect influences, like vasoconstriction or asphyxia. The gradual removal of these substances during sleep leads to a return to the waking state.

Impact of the vagal feedback on cardiorespiratory coupling in anesthetized rats.

Cardiorespiratory coupling can be significantly influenced by both pontine and vagal modulation of medullary motor and premotor areas. We investigated influences of the pontine intertrigeminal region (ITR) and peripheral vagal pathways on the coupling between systolic blood pressure (SBP) and respiration in 9 anesthetized rats. Glutamate injection into the ITR perturbed both respiration and SBP and decreased SBP-respiratory coherence (0.

Functional topography of respiratory, cardiovascular and pontine-wave responses to glutamate microstimulation of the pedunculopontine tegmentum of the rat.

Functionally distinct areas were mapped within the pedunculopontine tegmentum (PPT) of 42 ketamine/xylazine anesthetized rats using local stimulation by glutamate microinjection (10 mM, 5-12 nl). Functional responses were classified as: (1) apnea; (2) tachypnea; (3) hypertension (HTN); (4) sinus tachycardia; (5) genioglossus electromyogram activation or (6) pontine-waves (p-waves) activation.We found that short latency apneas were predominantly elicited by stimulation in the lateral portion of the PPT, in close proximity to cholinergic neurons.

Coupling changes in cortical and pontine sigma and theta frequency oscillations following monoaminergic lesions in rat.

Purpose: Sigma and theta frequency electroencephalogram (EEG) oscillations exhibit substantial and well-recognized shifts with transitions across sleep and wake states. We aimed in this study to test the changes in coupling between these characteristic oscillations of non-rapid-eye-movement (NREM)/rapid-eye-movement (REM) sleep within and between cortical and pontine EEGs following monoaminergic lesion, by using the Pearson's product-moment correlation coefficients.

Methods: Experiments were performed in 14 adult, male Sprague Dawley rats chronically instrumented for sleep recording.

Cardiorespiratory effects of intertrigeminal area stimulation in vagotomized rats.

It has been recently shown that the pontine intertrigeminal region (ITR) plays an important role in respiratory regulation, including vagally mediated apneic reflexes. Neurons of the ITR have connections with the nucleus tractus solitarius and projections to the ventrolateral medulla. However, the functional targets of these projections are not fully defined.

Local antagonism of intertrigeminal region metabotropic glutamate receptors exacerbates apneic responses to intravenous serotonin.

Injections of a broad spectrum glutamate receptor antagonist into the pontine intertrigeminal region (ITR) exacerbate vagal reflex apnea produced by intravenous serotonin infusion. This effect is not reproduced by ITR injections with either NMDA or AMPA receptor antagonists. Here, we tested the hypothesis that ITR injection with a metabotropic glutamate antagonist would alter respiratory responses to serotonin (5-HT) intravenous infusions.

Pharmacology of vagal afferent influences on disordered breathing during sleep.

Sleep-related breathing disorders (SRBD) are a significant public health concern, with a prevalence in the US general population of approximately 2% of women and approximately 4% of men. Although significant strides have been made in our understanding of these disorders with respect to epidemiology, risk factors, pathogenesis and consequences, work to understand these factors in terms of the underlying cellular, molecular and neuromodulatory processes remains in its infancy. Current primary treatments are surgical or mechanical, with no drug treatments available.

Monotone Signal Segments Analysis as a novel method of breath detection and breath-to-breath interval analysis in rat.

We applied a novel approach to respiratory waveform analysis--Monotone Signal Segments Analysis (MSSA) on 6-h recordings of respiratory signals in rats. To validate MSSA as a respiratory signal analysis tool we tested it by detecting: breaths and breath-to-breath intervals; respiratory timing and volume modes; and changes in respiratory pattern caused by lesions of monoaminergic systems in rats. MSSA differentiated three respiratory timing (tachypneic, eupneic, bradypneic-apneic), and three volume (artifacts, normovolemic, hypervolemic-sighs) modes.

[Is pharmacologic treatment of sleep apnea efficient?].

High frequency of sleep disturbed breathing in adults is increasingly recognized. Obstructive sleep apnea, defined as the recurring obstruction of the upper airway is documented in 24% of adult males and 9% of females. The highest incidence is in the sixth decade.

Impact of intertrigeminal region AMPA receptor blockade on respiratory responses in rats.

We hypothesized that functional glutamatergic AMPA receptors are expressed in the intertrigeminal region (ITR) of the lateral pons, and that blockade of these receptors by a specific AMPA receptor antagonist (NBQX) would alter respiratory responses both to ITR glutamate injections as well as to vagally mediated reflex apnea induced by intravenous infusion of serotonin. Non-selective blockade of ITR glutamate receptors using kynurenic acid previously was shown to alter both of these respiratory responses. Unilateral ITR injections in 19 anaesthetized spontaneously breathing adult Sprague-Dawley rats with the vagi intact demonstrated that NBQX (10mM): (1) shortened glutamate-induced apnea duration (p=0.

Efficacy of mirtazapine in obstructive sleep apnea syndrome.

Study Objectives: Decreased serotonergic facilitation of upper-airway motor neurons during sleep has been postulated as an important mechanism rendering the upper airway vulnerable to obstruction in patients with obstructive sleep apnea syndrome (OSA). Although serotonin reuptake inhibitors have been shown to produce modest reductions in the apnea-hypopnea index (AHI) during non-rapid eye movement (NREM) sleep, they have not been proven to be generally effective as treatments for OSA. Conversely, antagonists of type 3 (5-HT3) serotonin receptors effectively have been shown to reduce the frequency of central apneas during rapid eye movement (REM) sleep in a rodent model of sleep-related breathing disorder.

Modulation of respiratory pattern and upper airway muscle activity by the pedunculopontine tegmentum: role of NMDA receptors.

The pedunculopontine tegmental nucleus (PPT) is postulated to have important functions relevant to the regulation of rapid eye movement (REM) sleep and arousal, and various motor control systems including respiration. We have recently shown that pharmacologic activation of a neuronal subpopulation within the PPT, induced by micropipette injection of glutamate in nanoliter volumes, can produce respiratory rhythm disturbances and changes in genioglossus muscle activity in anesthetized rats. The aim of this study was to determine whether the respiratory pattern disturbance and increased genioglossus muscle tone induced by glutamate injection within the PPT are mediated by activation of N-methyl-D-aspartate (NMDA) receptors within the PPT.

Effects of intertrigeminal region NMDA and non-NMDA receptors on respiratory responses in rats.

Respiratory disturbance, including apnea, can be induced by microinjection of glutamate into the intertrigeminal region (ITR) of the lateral pons, a region that is anatomically coupled to both the dorsal and ventral respiratory groups of the medulla. We showed that the ITR plays a functional role in regulating both vagal reflex apnea and spontaneous sleep-related apnea in rats, but the mechanisms have not been determined. This study shows that functional NMDA receptors are expressed in the ITR since the blockade of these receptors by AP5, a specific NMDA receptor antagonist, was fully effective in blocking apnea induced by glutamate injection within this region.

Serotonin and noradrenaline modulate respiratory pattern disturbances evoked by glutamate injection into the pedunculopontine tegmentum of anesthetized rats.

Study Objectives: We hypothesized that 2 important neurotransmitters related to behavioral state control, serotonin and noradrenaline, could also be modulators of pedunculopontine tegmental nucleus (PPT)-induced respiratory dysrhythmia.

Design: We examined the impact of serotonin and noradrenaline at respiratory control sites in the PPT functionally identified by immediate apnea of 2.5- to 10-second duration, followed by increased variability of breath time (CVT(T)) (P < .

Injection of glutamate into the pedunculopontine tegmental nuclei of anesthetized rat causes respiratory dysrhythmia and alters EEG and EMG power.

The pedunculopontine tegmental nucleus (PPT) has been shown to have important functions relevant to the regulation of behavioral states and various motor control systems, including breathing control. Our previous work has shown that the activation of neurons within the PPT, a structure that is typically active during rapid eye movement (REM) sleep, can produce respiratory disturbances in freely moving and anesthetized rats. The aim of this study was to test the hypothesis that respiratory modulation by the PPT in anesthetized rats can be evoked in the absence of other signs of an REM-sleep-like state.

Modulation of reflex and sleep related apnea by pedunculopontine tegmental and intertrigeminal neurons.

We describe and summarize here our recent findings about the role in respiration of two pontine structures that are not classically included in the pontine respiratory group: the pedunculopontine tegmental nucleus (PPT) and the intertrigeminal region (ITR). We also discuss significant contributions of other workers in the field, especially, S. Datta [Cell.

Pontine intertrigeminal region attenuates sleep apneas in rats.

Study Objectives: To determine whether the pontine intertrigeminal region (ITR), with recently described anatomic connections and an effect on vagally induced reflex apnea, has an impact on spontaneous sleep apneas in rats.

Design: Respiration, electroencephalogram (EEG), and electromyogram (EMG) were recorded in rats with lesions of the pontine ITR and in control animals.

Participants: 9 adult male Sprague-Dawley rats.