Possible modulation of the medullary respiratory rhythm generator by the noradrenergic A5 area: an in vitro study in the newborn rat

doi:10.1016/0006-8993(89)90577-5

Brain Research

Volume 485, Issue 2, 24 April 1989, Pages 325-332

https://doi.org/10.1016/0006-8993(89)90577-5 Get rights and content

Respiratory activity was recorded on hypoglossal nerve or ventral cervical roots during in vitro experiments performed in the superfused brainstem-cervical cord preparation of newborn rats. Section and coagulation experiments revealed that the medullary respiratory generator was tonically inhibited by a structure located in the caudal ventrolateral pons. Electrical and pharmacological stimulations located this structure more precisely between the superior olivary nuclei and the sensory nucleus of the Vth nerve, i.e. in an area containing the A₅ noradrenergic nucleus. Norepinephrine and α₂-antagonists (yohimbine, idazoxan) added to the bathing medium modified the respiratory frequency. Norepinephrine decreased respiratory whereas norepinephrine antagonists increased respiratory rate. The electrical stimulation of the caudal ventrolateral pons which inhibited the respiratory rhythm under normal bathing medium became ineffective after α₂-antagonist. The results herein suggest that a noradrenergic inhibitory drive, originating from the A₅ area or surrounding structures modulates the activity of the medullary respiratory generator. This hypothesis is discussed in relation to A₅ involvement in cardiovascular regulation.

References (43)

AmaralD.G. et al.
The locus coeruleus: neurobiology of a central noradrenergic nucleus
Prog. Neurobiol.
(1977)
AndradeR. et al.
Single cell activity in the noradrenergic A5 region: responses to drugs and peripheral manipulations of blood pressure
Brain Research
(1982)
ByrumC. et al.
Electrophysiological properties of spinally-projecting A₅ noradrenergic neurons
Brain Research
(1984)
ChampagnatJ. et al.
Catecholaminergic depressant effects on bulbar respiratory mechanisms
Brain Research
(1979)
CloseJ.M. et al.
Actions of N-methyl aspartate and its antagonist aminophosphonovalerate on the A₅ catecholamine cell group in the rat
Brain Research
(1982)
FreedmanJ.E. et al.
Idazoxan (RX 781094) selectively antagonizes alpha-2 adrenoreptors on rat central neurons
Eur. J. Pharmacol.
(1984)
GuyenetP.G.
Baroreceptor-mediated inhibition of A₅ noradrenergic neurons
Brain Research
(1984)
GuyenetP.G. et al.
Projection of nucleus paragigantocellularis lateralis to locus coeruleus and other structures in rat
Brain Research
(1987)
HaradaY. et al.
Central chemosensitivity to H⁺ and CO₂ in the rat respiratory center in vitro
Brain Research
(1985)
KesslerJ.P. et al.
Inhibitory influence of monoamines and brainstem monoaminergic regions on the meduallry swolling reflex
Neurosci. Lett.
(1986)

KoepchenH.P. et al.

The problem of identification of autonomic neurons in the lower brain stem

Brain Research

(1975)

LanghorstP. et al.

Reticular formation of the lower brainstem. A common system for cardiorespiratory and somatomotor functions: discharge patterns of neighbouring neurons influenced by cardiovascular and respiratory influences

J. Auton. Nerv. Syst.

(1983)

MediavillaA. et al.

The stimulatory action ofd-amphetamine on the respiratory and its mediation by a central alpha-adrenergic mechanism

Neuropharmacology

(1979)

MurakoshiT. et al.

Respiratory reflexes in an isolated brainstem-lung preparation of the newborn rat: possible involvement of gamma-aminobutyric acid and glycine

Neurosci. Lett.

(1985)

PalkovitsM. et al.

Neuroanatomy of central cardiovascular control. Nucleus tractus solitarii: afferent and efferent neuronal connections in relation to the baroreceptor reflex arc

QuintinL. et al.

Variations in DOPAC concentration are correlated to single cell firng changes in the rat locus coeruleus

Neuroscience

(1986)

SaetherK. et al.

Dorsal and ventral respiratory groups of neurons in the medulla of the rat

Brain Research

(1987)

VibertJ.F. et al.

Three-dimensional representation of bulbo-pontine respiratory networks architecture from density maps

Brain Research

(1976)

BolmeP. et al.

Pharmacological studies on a possible role of central norepinephrine neurons in respiratory control

J. Pharm. Pharmacol.

(1973)

BrownD.L. et al.

Electrophysiological study of cardiovascular neurons in the rostnal ventrolateral medulla in rats

Circ. Res.

(1985)

BrunnerM.J. et al.

Interaction of carotid chemoreceptor and baroreceptor reflexes in anesthetized dogs

Am. J. Physiol.

(1988)

Cited by (124)

Effect of temperature, age and the pons on respiratory rhythm in the rat brainstem-spinal cord
2020, Respiratory Physiology and Neurobiology
Citation Excerpt :
At 27 °C (our baseline condition), descending inputs from the pons significantly reduced the fictive respiratory frequency of the older brainstem-spinal cord preparations but not the younger preparations. This is consistent with results from other studies (Corcoran and Milsom, 2009; Fong et al., 2008; Hilaire et al., 1989, 2004; Errchidi et al., 1990, 1991). Corcoran and Milsom (2009) reported that at P0 the pons provides an excitatory input that disappears by P2 and is replaced by an inhibitory input by P4.
Neonatal animals are extremely tolerant of hypothermia. However, cooling will ultimately lead to ventilatory arrest, or cessation of respiratory movements. Upon rewarming, ventilation can recover spontaneously (autoresuscitation). This study examined the effect of age (P0-P5) and the pons on respiratory-related output during hypothermic ventilatory arrest and recovery using a brainstem-spinal cord preparation of neonatal rats. As temperature fell, burst frequency slowed, burst duration increased, burst shape became fragmented and eventually respiratory arrest occurred in all preparations. Removing the pons had little effect on younger preparations (P0-P2). Older preparations (P4-P5) with the pons removed continued to burst at cooler temperatures compared to pons-intact preparations and burst durations were significantly longer. Episodic breathing patterns were observed in all preparations (all ages, pons on or off) at lower temperatures. At 27 °C, however, episodic breathing was only observed in younger preparations with the pons on. These data suggest that developmental changes occurring at the level of the pons underlie the loss of hypothermic tolerance and episodic breathing.
Role of A5 noradrenergic neurons in the chemoreflex control of respiratory and sympathetic activities in unanesthetized conditions
2017, Neuroscience
The A5 area at the ventrolateral pons contains noradrenergic neurons connected with other medullary areas involved in the cardiorespiratory control. Its contribution to the cardiorespiratory regulation was previously evidenced in anesthetized conditions. In the present study, we investigated the involvement of the A5 noradrenergic neurons to the basal and chemoreflex control of the sympathetic and respiratory activities in unanesthetized conditions. A5 noradrenergic neurons were lesioned using microinjections of anti-dopamine β-hydroxylase saporin (anti-DβH-SAP). After 7–8 days, we evaluated the arterial pressure levels, heart rate and minute ventilation in freely moving adult rats (280–350 g) as well as recorded from thoracic sympathetic (tSN) and phrenic nerves (PN) using the arterially perfused in situ preparation of juvenile rats (80–90 g). Baseline cardiovascular, sympathetic and respiratory parameters were similar between control (n = 7–8) and A5-lesioned rats (n = 5–6) in both experimental preparations. In adult rats, lesions of A5 noradrenergic neurons did not modify the reflex cardiorespiratory adjustments to hypoxia (7% O₂) and hypercapnia (7% CO₂). In the in situ preparations, the sympatho-excitation, but not the PN reflex response, elicited by either the stimulation of peripheral chemoreceptors (ΔtSN: 110 ± 12% vs 58 ± 8%, P < 0.01) or hypercapnia (ΔtSN: 9.5 ± 1.4% vs 3.9 ± 1.7%, P < 0.05) was attenuated in A5-lesioned rats compared to controls. Our data demonstrated that A5 noradrenergic neurons are part of the circuitry recruited for the processing of sympathetic response to hypoxia and hypercapnia in unanesthetized conditions.
Dynamic changes in phrenic motor output following high cervical hemisection in the decerebrate rat
2015, Experimental Neurology
Hemisection of the spinal cord at C₂ eliminates ipsilateral descending drive to the phrenic nucleus and causes hemidiaphragmatic paralysis in rats. Phrenic nerve (PhN) or diaphragmatic activity ipsilateral to hemisection can occasionally be induced acutely following hemisection by respiratory stressors (i.e., hypercapnia, asphyxia, contralateral phrenicotomy) and becomes spontaneously active days-to-weeks later. These investigations, however, are potentially confounded by the use of anesthesia, which may suppress spontaneously-active crossed phrenic pathways. Experiments were performed on vecuronium-paralyzed, unanesthetized, decerebrate adult male rats and whole PhN activity recorded continuously before, during, and after high cervical hemisection at the C₁ spinal level. Crossed phrenic activity recovered spontaneously over minutes-to-hours with maximal recovery of 11.8 ± 3.1% (m ± SE) in the PhN ipsilateral to hemisection. Additionally, there was a significant increase in PhN activity contralateral to hemisection of 221.0 ± 40.4% (m ± SE); since animals were artificially-ventilated, these changes likely represent an increase in central respiratory drive. These results underscore the state-dependence of crossed bulbophrenic projections and suggest that unanesthetized models may be more sensitive in detecting acute recovery of respiratory output following spinal cord injury (SCI). Additionally, our results may suggest an important role for a group of C₁–C₂ neurons exhibiting respiratory-related activity, spared by the higher level of hemisection. These units may function as relays of polysynaptic bulbophrenic pathways and/or provide excitatory drive to phrenic motoneurons. Our findings provide a new model for investigating acute respiratory recovery following cervical SCI, the high C₁-hemisected unanesthetized decerebrate rat and suggest a centrally-mediated increase in central respiratory drive in response to high cervical SCI.
The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures
2014, Neuroscience Letters
Citation Excerpt :
Mean fR was significantly different between MS (8.95 ± 0.21 bursts • min−1, n = 54) and DBS (5.22 ± 0.14 bursts • min−1, n = 56; p < 0.0001) preparations in line with previous data [23]. The moderating effect of supramedullary areas may depend on the pontine A5 region, which is known to decrease fR [25] and/or other supramedullary areas such as those included in the mesencephalon, which exert a moderating effect on neurons of the ventrolateral reticular nucleus of the medulla oblongata encompassing the ventral respiratory group [24]. Under normal pH conditions, the fR of MS preparations was significantly increased by acute exposure to ETO (+29.68 ± 14.41%, n = 8, p < 0.05; Fig. 2(B1 and B2)), but was not significantly changed by exposure to DMSO (+8.64 ± 5.18%, n = 14; Fig. 2(A1 and A2)).
Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO₂/H⁺ chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO₂/H⁺ chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions.
Chronic serotonin-norepinephrine reuptake transporter inhibition modifies basal respiratory output in adult mouse in vitro and in vivo
2012, Respiratory Physiology and Neurobiology
Respiratory disturbances are a common feature of panic disorder and present as breathing irregularity, hyperventilation, and increased sensitivity to carbon dioxide. Common therapeutic interventions, such as tricyclic (TCA) and selective serotonin reuptake inhibitor (SSRI) antidepressants, have been shown to ameliorate not only the psychological components of panic disorder but also the respiratory disturbances. These drugs are also prescribed for generalized anxiety and depressive disorders, neither of which are characterized by respiratory disturbances, and previous studies have demonstrated that TCAs and SSRIs exert effects on basal respiratory activity in animal models without panic disorder symptoms. Whether serotonin–norepinephrine reuptake inhibitors (SNRIs) have similar effects on respiratory activity remains to be determined. Therefore, the current study was designed to investigate the effects of chronic administration of the SNRI antidepressant venlafaxine (VHCL) on basal respiratory output. For these experiments, we recorded phrenic nerve discharge in an in vitro arterially-perfused adult mouse preparation and diaphragm electromyogram (EMG) activity in an in vivo urethane-anesthetized adult mouse preparation. We found that following 28-d VHCL administration, basal respiratory burst frequency was markedly reduced due to an increase in expiratory duration (T_E), and the inspiratory duty cycle (T_I/T_tot) was significantly shortened. In addition, post-inspiratory and spurious expiratory discharges were seen in vitro. Based on our observations, we suggest that drugs capable of simultaneously blocking both 5-HT and NE reuptake transporters have the potential to influence the respiratory control network in patients using SNRI therapy.
The brainstem respiratory network: An overview of a half century of research
2009, Respiratory Physiology and Neurobiology
This review aims at summarizing the work performed over 40 years by Professor Armand Bianchi and the research team he directed, which was devoted to the study of the central respiratory network. The major steps towards the understanding of this complex network will be presented together with methodological considerations. This includes the sequential progress that was made in the identification and characterization of respiratory neurons as deduced from inferences gleaned from intracellular recordings, which revealed putative synaptic connections within the respiratory network. Also reviewed is a comparison of in vivo versus in vitro approaches. The search for the “real” respiratory neurons must consider that those neurons are redundantly represented within the brainstem and express a wide variety of patterns. The last part of this review focuses on the concept that the brainstem respiratory circuitry forms part of a multifunctional network subserving both respiration and non-respiratory motor behaviors. Numerous data provide evidence that the respiratory network operates as a dynamic assembly of neurons, some of which can belong to several networks involved in the coordination of respiratory muscles during functions that include coughing, swallowing and vomiting.

View all citing articles on Scopus

View full text

Possible modulation of the medullary respiratory rhythm generator by the noradrenergic A5 area: an in vitro study in the newborn rat

Prog. Neurobiol.

Brain Research

Brain Research

Brain Research

Brain Research

Eur. J. Pharmacol.

Brain Research

Brain Research

Brain Research

Neurosci. Lett.

Brain Research

J. Auton. Nerv. Syst.

Neuropharmacology

Neurosci. Lett.

Neuroscience

Brain Research

Brain Research

Pharmacological studies on a possible role of central norepinephrine neurons in respiratory control

J. Pharm. Pharmacol.

Electrophysiological study of cardiovascular neurons in the rostnal ventrolateral medulla in rats

Circ. Res.

Interaction of carotid chemoreceptor and baroreceptor reflexes in anesthetized dogs

Am. J. Physiol.

Possible modulation of the medullary respiratory rhythm generator by the noradrenergic A₅ area: an in vitro study in the newborn rat