Serotonin 1A-receptor activation suppresses respiratory apneusis in the cat

doi:10.1016/0304-3940(94)90662-9

Neuroscience Letters

Volume 172, Issues 1–2, 19 May 1994, Pages 59-62

https://doi.org/10.1016/0304-3940(94)90662-9 Get rights and content

Abstract

Malfunction of inhibitory synaptic processes in the brainstem result in abnormal prolonged inspiration (apneusis). Since we previously found that the serotonin (5-hydroxytryptamine; 5-HT) 5-HT_1A receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) shortens inspiratory discharges, we tested its ability to suppress apneusis. We recorded phrenic nerve activity and the membrane potential of medullary expiratory (E-2) and postinspiratory (PI) neurons in 14 anaesthetized, paralyzed, artifically ventilated cats. Systemic hypoxia or i.v. injection of pentobarbital sodium or the $N- methyl- d -aspartate$ (NMDA) receptor blocker ketamine induced apneustic phrenic nerve discharges, delayed depolarization to threshold of E-2 neurons and prolonged hyperpolarization in PI neurons. 8-OH-DPAT (10–40 μg/kg i.v.) produced partial to complete restoration of normal phrenic nerve discharges and membrane potential.

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Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among patients with epilepsy. However, the underlying mechanism of SUDEP remains elusive. Previous studies showed seizure-induced respiratory arrest (S-IRA) is the main factor in SUDEP, and that enhancement of serotonin (5-HT) function in the dorsal raphe nucleus (DR) can significantly reduce the incidence of S-IRA in the DBA/1 mouse model of SUDEP. The pre-Bötzinger complex (PBC), known for its role in regulating respiratory rhythm, can express the 5-HT2A receptor (5-HT2AR). Here, using the pharmacological and optogenetic methods, respectively, we observed that the serotonergic neural circuit between DR and PBC was involved in S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) injection in the DBA/1 mice, and found 5-HT2AR located in PBC plays an important role in it. Our findings will further significantly improve our understanding of SUDEP and provide a promising therapeutic target for SUDEP prevention.
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In decerebrated dogs 8-OH-DPAT shortened both phases of respiratory cycle, while picoinjections to pre-BötC had no detectable effect on respiratory rate (Radocaj et al., 2015). Systemic injection of this agent unleashed inspiratory medullary neurons from apnoeic discharges but depressed activity of expiratory ones (Lalley et al., 1994a, 1994b). Stimulation of peripheral 5HT1A receptors of rats by systemic injection of 8-OH-DPAT increased tidal volume and breathing rate outside of the vagi, with contribution of the carotid sinus nerves to the frequency response (Szereda-Przestaszewska and Kaczyńska, 2007).
Numerous neurotransmitters identified in the central nervous system play role in ventilatory control. This mini-review focuses on the respiratory effects of two neurotransmitters: serotonin (5-HT) and substance P (SP). We discuss their co-localization in medullary raphe nuclei, expression of proper receptors within the specific regions of respiratory related structures and contribution to respiratory rhythmogenesis.
Dose-effect study of the serotonin agonist R-8-OH-DPAT on opioid-induced respiratory depression in blesbok (Damaliscus pygargus philipsi) and impala (Aepyceros melampus)
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To determine whether the R-enantiomer of 8-hydroxy-2-(di-n-propylamino) tetralin (R-8-OH-DPAT) alleviates respiratory depression in antelope species immobilized with etorphine. The experiment also aimed to establish the most clinically effective dose of this serotonin 5- HT_1A receptor agonist.
A group of six female blesbok and six female impala.
Each animal was subjected to four immobilization treatments in a prospective four-way crossover design—control treatment consisting of only etorphine at 0.09 mg kg^–1 and three treatments consisting of etorphine at 0.09 mg kg^–1 combined with 0.005, 0.02 and 0.07 mg kg^–1 of R-8-OH-DPAT, respectively. Induction, quality of immobilization and recovery were monitored in each treatment. Physiological variables including heart rate, respiratory rate, arterial blood pressure and blood gases were measured for 35 minutes during immobilization. A linear mixed model was used to assess the effects of treatments over the recumbency period.
R-8-OH-DPAT did not influence induction, immobilization or recovery scores. Respiratory rate in blesbok was increased in the medium- and high-dosage R-8-OH-DPAT treatment group. However, this increased respiratory rate did not translate into improvements of arterial partial pressure of oxygen (PaO₂) values in the blesbok. The medium and higher dosages of R-8-OH-DPAT in impala led to an improved PaO₂ as well as to decreased opioid-induced tachycardia during the first 10 minutes of immobilization.
Previous reports indicated that the racemic mixture of 8-OH-DPAT injected intravenously had a positive effect on blood-gas values in etorphine-treated hypoxemic goats. In this experiment, similar effects could be seen in impala at the higher dosage rates of R-8-OH-DPAT. However, failure to achieve an improvement of blood-gas values in blesbok was an unexpected result. It could be speculated that the dosage, species-specific differences of serotonin receptors or the use of the R-enantiomer of 8-OH-DPAT might play a role.
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The reversal of morphine-induced apnoea in conscious and anaesthetised rats with 5-HT1A receptor agonist (8-OH-DPAT) was first described by Sahibzada et al. [101], and appeared likewise effective in averting fentanyl respiratory depression of in situ preparation [102,103] and apnoea in intact anaesthetised rats [40]. This serotonergic ligand given intravenously suppressed medullary respiratory neuron discharges and phrenic nerve discharges [64,65]. Mention should be made here of an increased tidal volume induced by systemic injection of 8-OH-DPAT in vagotomised rats [104], particularly as it permeates the blood-brain barrier [105].
This review analyses the knowledge about the incidence of transient apnoeic spells, induced by substances which activate vagal chemically sensitive afferents. It considers the specificity and expression of appropriate receptors, and relevant research on pontomedullary circuits contributing to a cessation of respiration. Insight is gained into an excitatory drive of 5-HT_1A serotonin receptors in overcoming opioid-induced respiratory inhibition.
Effect of serotonin 1A agonists and selective serotonin reuptake inhibitors on behavioral and nighttime respiratory symptoms in rett syndrome
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In contrast to the expiration-exaggerated central apnea, another type of respiration known as apneusis can occur in patients with Rett syndrome. Apneusis is characterized by a prolonged inspiratory phase, caused by augmented and prolonged decrementing inspiratory (e-I in) neuronal activity.11 Disturbance of the expiration–inspiration transition results in central apnea, whereas disturbance of the inspiration–expiration transition causes apneusis.
Rett syndrome is characterized by psychomotor regression during early childhood, autistic-like behaviors, and aberrant breathing patterns. Dysfunction of the serotonergic system has been postulated to play a role in the pathophysiology of these symptoms.
We present an 11-year-old girl with Rett syndrome who exhibited marked respiratory symptoms, including frequent apneic events during sleep. She had been treated for these respiratory symptoms using noninvasive positive pressure ventilation since age six years. Treatment with serotonin 1A receptor agonist was initiated at age eight years, whereas treatment using a selective serotonin reuptake inhibitor began at age nine years. Noninvasive positive pressure ventilation therapy was effective in reducing symptoms of sleep apnea, and administration of serotonergic agents resulted in amelioration of sleep apneic events even in the absence of noninvasive positive pressure ventilation. In addition, improvements in hand stereotypy and social skills were observed after initiation of serotonin-based therapy.
The respiratory difficulties our patient experienced during non-rapid eye movement (REM) sleep are characteristic of post-sigh central apnea. Exaggerated activity of expiratory neurons during such apneic events has been observed in mouse models of Rett syndrome. We suggest that prescribed serotonergic agents might serve to inhibit such activity, attenuating the imbalance between inspiratory and expiratory neurons. These agents might also be useful in the treatment of autistic-like behaviors caused by impaired serotonergic transmission in the brain.
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2014, Neuronal Networks in Brain Function, CNS Disorders, and Therapeutics
As discussed in this book, there are many primary neuronal networks that mediate important physiological functions of the central nervous system (CNS), including vision, hearing, locomotion, and respiration. Each of these normal networks can interact with other primary networks to mediate important cross-network functions, and the interaction can be either additive or competitive. An example of an additive or positive form of network interaction is seen in sensorimotor integration, including the visual-motor interactions that mediate eye movements in response to visual stimuli. Primary networks can also interact with nonprimary conditional multireceptive networks, leading to the emergence of more complex phenomena. These phenomena include certain forms of learning as well as CNS disorders, including, for example, those that can lead to death in epilepsy. Neuronal networks can compete with each other to reduce the network function. This occurs, for example, when an acoustic stimulus can induce cessation of locomotion in a learning paradigm such as fear conditioning. A negative interaction is also seen in the prototypical competitive network interaction that forms the basis of the original and conceptually important network interaction hypothesis, the gate control theory of pain. This network competition mechanism is proposed to be a critical mechanism mediating the therapeutic stimulation paradigms currently used to treat many CNS disorders. Network interactions are mediated by (1) direct electrophysiological connections between network neurons that release endogenous neuroactive substances via synaptic transmission and (2) indirect interactions that release these substances via volume transmission. These network interactions can occur essentially instantaneously or sequentially over a finite time course. The interactions can involve two networks, as in the somatosensory-motor network interactions, which occur in the tactile startle response, and are also seen in the interaction of the pain network with the therapeutic network initiated by certain pain-relieving electrical stimulation therapies. The network interactions can be more complex, involving three or more networks, and examples of multinetwork interaction include fear-potentiated startle, seizure-induced analgesia, and audiogenic seizure kindling. An example of such a multinetwork interaction with fatal consequences is proposed to occur in the CNS disorder of epilepsy called sudden unexpected death in epilepsy (SUDEP). The DBA/1 and DBA/2 mouse models of SUDEP involve additive interactions between the auditory and locomotor networks and a subsequent negative interaction with the respiratory network, which results in respiratory arrest. These network interactions may be mediated, in part, by the release of endogenous neuroactive substances that inhibit (e.g. adenosine) or enhance (e.g. serotonin) the activity of the respiratory network via synaptic and/or volume transmission. Thus, investigations of network interactions in normal situations and in CNS disorders may provide the keys to understanding learning mechanisms and also for treating CNS disorders with stimulation and/or pharmacological paradigms.

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^☆: This work was supported by the Deutsche Forschungsgemeinschaft and the National Institute of Health

^∗∗: Acknowledged for assistance.

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Serotonin 1A-receptor activation suppresses respiratory apneusis in the cat☆

Abstract

Prog. Neurobiol.

Neurosci. Lett.

Neurosci. Lett.

Neurosci. Lett.

Neurosci. Lett.

Brain Res.

Opposing effects of 5-hydroxytryptamine on two types of medullary inspiratory neurons with distinct firing patterns

Neurophysiology

Inhibition of the activity of the respiratory and vasomotor centers by centrally administered 5-hydroxy-tryptamine in cats

Rev. Esp. Fiziol.

The non-uniform character of expiratory synaptic activity in expiratory bulbospinal neurones of the cat

J. Physiol.

Synaptic interaction between medullary respiratory neurones during apneusis induced by NMDA-receptor blockade in cat

J. Physiol.

Serotoninergic and non-serotoninergic responses of phrenic motoneurones to stimulation of raphe nuclei in the cat

J. Physiol.