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Miodrag Radulovacki

Publications and source records attributed to Miodrag Radulovacki.

13 recordsLinked to original sources
PubMed2006

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. Selective blockade of ITR NMDA receptors had no effect on the immediate apnea evoked by an intravenous 5-HT bolus, whereas the nonspecific glutamate receptor antagonist kynurenic acid significantly increased the duration of this vagal reflex apnea. These findings are of interest because pontine NMDA receptors participate in inspiratory off-switch mechanisms and have been implicated in various short- and long-term potentiation and depression phenomena. These data support the involvement of ITR non-NMDA receptors in modulation of reflex apnea per se, whereas NMDA receptors play a role in damping respiratory responses to transient disturbances.

2-Amino-5-phosphonovalerate↗
PubMed2006

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. Experiments were performed in eight adult male spontaneously breathing Sprague-Dawley rats anesthetized using nembutal. Respiratory movements were monitored by piezoelectric strain gauge. Three-barrel glass pipettes were used to pressure inject glutamate (as a probe for respiratory modulating sites), ketamine (an NMDA channel blocker), and oil-red dye (to aid in histological verification of the injection sites) within the PPT. Electroencephalograms were recorded from the sensorimotor cortex, the hippocampus, and the pons, contralateral to the injection site. Electromyograms (EMGs) were recorded from the genioglossus muscle. The typical response to glutamate injection within the PPT respiratory-modulating region was immediate apnea followed by tachypnea and increased genioglossal tonic activity. The noncompetitive NMDA receptor channel-antagonist ketamine, injected at the same site and in the same volume as glutamate (5 nl), blocked respiratory dysrhythmia and genioglossal EMG responses to subsequent glutamate injections. For the first time, the present results suggest that respiratory rhythm and upper airway muscle tone are controlled by the activation of pedunculopontine tegmental nucleus NMDA receptors.

Animals↗
PubMed2005

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. We characterized electroencephalogram (EEG) and electromyogram (EMG) changes during respiratory disturbances induced by glutamatergic stimulation of the PPT in spontaneously breathing, adult male Sprague-Dawley rats anesthetized with a ketamine/xylazine combination or with nembutal. Respiratory movements were monitored by a piezoelectric strain gauge. Two-barrel glass pipettes were used to pressure inject glutamate, to probe for respiratory effective sites within the PPT, and to inject oil red dye at the end of the experiments for histological verification of the injection sites. The EEGs were recorded from the sensorimotor cortex, hippocampus, and from the pons contralateral from the injection site. The EMGs were recorded from the genioglossus muscle. The initial response to glutamate injection into the respiratory modulating region of the PPT was always a respiratory pattern disturbance. Subsequent activation of EMG and EEG often occurred in ketamine/xylazine-anesthetized rats, but REM-sleep-like patterns were not observed. Respiratory pattern and EMG power changes in nembutal-anesthetized rats were similar, but EEG activation was never observed. Thus, we conclude that respiratory suppression produced by the local activation of PPT neurons may not necessarily be accompanied by an REM-sleep-like cortical state in this anesthetized model.

Anesthesia↗
PubMed2005

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 < .04) after locally injecting glutamate in anesthetized rats. SETTING: Basic sleep and respiratory neurobiology laboratory. PARTICIPANTS: Sixteen adult, male Sprague-Dawley rats. MEASUREMENTS AND RESULTS: Glutamate-induced respiratory responses, including increases of total apnea duration and CVT(T), were not different between groups of rats in which we further tested monoaminergic modulatory effects (for CVT(T) P = .98, and for total apnea duration, P = .80). Serotonin or noradrenaline injected at the same sites as glutamate had equal impact on CVT(T) (P = .34) and on mean total apnea duration (P = .80), but pretreatment of PPT sites with serotonin blocked (remained equal to preinjection; P = .11), whereas pretreatment with noradrenaline potentiated (P = .04) the increment of respiratory-timing variability induced by glutamate. The serotonergic-blocking effect on glutamate-induced respiratory dysrhythmia was specific to the PPT: the respiratory responses induced by glutamate injection outside the PPT were not modulated by serotonin (for CVT(T), P = .46, and for mean apnea duration, P = .99). CONCLUSIONS: The opposed impact of serotonin and noradrenaline on PPT-induced respiratory dysrhythmia, in contrast to their convergent regulatory role in behavioral state control, suggests a functionally distinct role for the PPT in respiratory-pattern control independent of rapid eye movement sleep control.

Anesthesia↗
PubMed2004

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. Mol. Neurobiol. 17: 341-365, 1997], R. Lydic and H. Baghdoyan [Sleep, 25: 617-622, 2002], and N. Chamberlin and C. Saper [J. Neurosci. 18: 6048-6056, 1998], who postulated a role for the ITR in modulating reflex apnea. In anesthetized and freely moving rats we have consistently documented that PPT and ITR have a role in respiration. Neurochemical manipulations of each area affected the brainstem respiratory pattern generator and respiratory pattern variability,observed as spontaneous disturbances during sleep or as induced reflex apnea. Although the exact central mechanisms of apnea cannot be determined from our studies to date, we postulate that reflex and sleep-related apneas in rats share some common brainstem pathways, which may include PPT and ITR.

Animals↗
PubMed2004

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. INTERVENTIONS: Rats were implanted with EEG and EMG electrodes and were polygraphically recorded for 6 hours, and their respiration was monitored by placing each animal inside a single-chamber plethysmograph. Subsequently, a respiratory-related intertrigeminal site was identified by probing on dorsoventral tracks with 2 to 5 nL glutamate (10 nL, 10 mmol) injections from a multibarrel glass pipette. This site was then lesioned by injecting ibotenic acid (10 nL, 50 mmol) from a second pipette barrel. Animals were again recorded for 6 hours on days 2, 7, and 14 after the lesion. MEASUREMENTS AND RESULTS: ITR lesions exerted no impact on mean respiratory pattern during any sleep-wake state, compared to baseline recordings. In contrast, apnea frequency during non-rapid eye movement sleep increased following ITR lesion, more than doubling by day 14. CONCLUSIONS: This study demonstrates that a small and well-localized unilateral lesion of the ITR region in the lateral pons can increase sleep apnea expression in freely moving rats over a 2-week period. The present findings are in agreement with the general modulatory role of pontine structures in activities including respiration, heart rate, and regulation of blood pressure.

Animals↗
PubMed2003

Respiratory pattern modulation by the pedunculopontine tegmental nucleus.

This study demonstrates respiratory modulation caused by stimulation of the pedunculopontine tegmental nucleus (PPT), a structure not classically included in the pontine respiratory neuronal network. The long-lasting increase in variability of respiratory parameters following glutamate microinjection into PPT in anesthetized, spontaneously breathing Sprague Dawley rats was more pronounced under ketamine than nembutal anesthesia. The induced respiratory perturbations were characterized by intermittent apneas and increased variability of expiratory (TE) and total (TT) breath durations in all animals. Although the baseline spontaneous breathing patterns (mean values of all respiratory parameters and their variabilities) were equivalent under ketamine and nembutal anesthesia, different anesthetic agents did affect respiratory responses to PPT stimulation by glutamate in terms of latency, duration, and structure. We conclude that glutamatergic stimulation of PPT has a significant impact on the brainstem respiratory pattern generator.

Analysis of Variance↗
PubMed2003

An automated pontine-wave detection system.

STUDY OBJECTIVES: Pontine-waves (P-waves), the pontine component of ponto-geniculo-occipital waves, represent a close marker of brainstem phasic events and are associated with cardiorespiratory changes in sleep. Because visual scoring is subjective and cumbersome, we developed an automated P-wave analysis system, which could detect and classify P-waves as clusters or as isolated events in bipolar recordings of the pontine electroencephalogram (EEG) of conscious rats. DESIGN: A computer algorithm was developed to extract and normalize each half-wave of the pontine EEG according to the background noise level. Candidate events for different P-wave patterns (uniphasic, biphasic, and triphasic) were compared to a corresponding set of amplitude and duration thresholds to identify P-waves and to reject artifacts. PARTICIPANTS: Ten adult male Sprague-Dawley rats were instrumented for chronic polysomnography. MEASUREMENTS AND RESULTS: Two human experts manually scored each recording, and their consensus score was used as the "gold standard" for algorithm optimization and validation. The algorithm's scoring thresholds were optimized on a training set of 5 six-hour polysomnographic records, yielding 96.8% accuracy and 97.7% sensitivity versus human consensus scoring. Validation of the algorithm, using the optimized threshold values, was conducted using a set of 5 independent recordings, resulting in 94.8% accuracy and 94.7% sensitivity versus human consensus scoring. CONCLUSIONS: We have developed and validated an automated system for detection and classification of P-waves in conscious rats with advantages over human scoring, including increased speed and perfect reliability.

Algorithms↗
PubMed2003

Intertrigeminal region attenuates reflex apnea and stabilizes respiratory pattern in rats.

The goal of the present study was to determine whether the newly described anatomical pathway involving the pontine intertrigeminal region (ITR), (Chamberlin and Saper, 1998), has a physiological role in mediating or modulating vagally-induced reflex apnea. We explored the ITR impact on vagal reflex apnea elicited by intravenuously injected 5-HT in ten anesthetized rats. The animals had a catheter inserted into the femoral vein for administration of 5-HT (0.00375 mg) and respiration was recorded by piezo-electric crystal. Multibarrel pipettes were used to pressure inject glutamate (5-10 nl, 10 mM), kynurenic acid (10 nl, 50 mM, a glutamate receptor antagonist), and red dye into the ITR, unilaterally and bilaterally. Intravenous administration of 5-HT produced an immediate 3-s apnea. Microinjections of glutamate into the ITR produced apneas, while microinjections of kynurenic acid blocked the glutamate effect. Following glutamate antagonism, subsequent administration of 5-HT produced apneas of much longer duration (8 s). Acute ponto-medullary transection in two animals yielded even greater prolongation of 5-HT-induced apnea. We conclude that a physiological role for the ITR in respiration is to attenuate vagally-induced reflex apneas. This finding is in agreement with the general modulatory role of pontine structures in autonomic activities including respiration, heart rate and regulation of blood pressure. In addition, our data indicate that medullary circuits, independent of pontine structures, are sufficient to produce 5-HT induced reflex apnea.

Animals↗
PubMed2002

Functional role for cannabinoids in respiratory stability during sleep.

STUDY OBJECTIVES: Serotonin, acting in the peripheral nervous system, can exacerbate sleep-related apnea, and systemically administered serotonin antagonists reduce sleep-disordered respiration in rats and bulldogs. Because cannabinoid receptor agonists are known to inhibit the excitatory effects of serotonin on nodose ganglion cells, we examined the effects of endogenous (oleamide) and exogenous (delta9-tetrahydrocannabinol; delta9THC) cannabimimetic agents on sleep-related apnea. DESIGN: Sleep architecture, respiratory pattern, and apnea expression in rats were assessed by polysomnography. A repeated measures, within-subjects, fully nested crossover design was used in which each animal was recorded on exactly 12 occasions. PARTICIPANTS: Eleven adult male Sprague-Dawley rats were instrumented for chronic polysomnography. INTERVENTIONS: Animals were recorded following intraperitoneal injection of various doses of delta9THC, oleamide, and serotonin, alone and in combination. MEASUREMENTS AND RESULTS: Our data show that delta9THC and oleamide each stabilized respiration during all sleep stages. With delta9THC, apnea index decreased by 42% (F=2.63; p=0.04) and 58% (F=2.68; p=0.04) in NREM and REM sleep, respectively. Oleamide produced equivalent apnea suppression. This observation suggests an important role for endocannabinoids in maintaining autonomic stability during sleep. Oleamide and delta9THC blocked serotonin-induced exacerbation of sleep apnea (p<0.05 for each), suggesting that inhibitory coupling between cannabinoids and serotonin receptors in the peripheral nervous system may act on apnea expression. CONCLUSIONS: This study demonstrates potent suppression of sleep-related apnea by both exogenous and endogenous cannabinoids. These findings are of relevance to the pathogenesis and pharmacological treatment of sleep-related breathing disorders.

Animals↗