The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances

Dutschmann, Mathias; Waki, Hidefumi; Manzke, Till; Simms, Annabel E.; Pickering, Anthony E.; Richter, D. W.; Paton, Julian F. R.

doi:10.1098/rstb.2009.0076

Cited by 41 publications

(34 citation statements)

References 55 publications

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“…This inhibitory effect has been demonstrated in late-E neurons of anesthetized cats (12) and most likely contributes to the effects seen with 8-OH-DPAT. More recently it has been shown that the glycinergic inhibitor strychnine abolishes the effects of 8-OH-DPAT in rats studied in situ (14). Thus glycine-mediated inhibition may also add to the correction of respiratory disturbances seen with the serotonin 1a agonist.…”

Section: Mechanism Of Serotonin 1a Agonist Induced Inhibition Of Expimentioning

confidence: 99%

“…Because serotonin 1a receptor agonists have been shown to both inhibit expiratory neurons (12) and reinstate breathing after opioid-induced central apneas (13,14), we tested whether 8-hydroxy-dipropyl-aminotetralin (8-OH-DPAT) (a serotonin 1a receptor agonist) could depress the respiratory apneas in Mecp2 heterozygote mice. Our findings reveal that both treatments significantly reduced apneas and periodic breathing in Mecp2-deficient mice and restored regularity to their cycle intervals.…”

mentioning

confidence: 99%

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Correction of respiratory disorders in a mouse model of Rett syndrome

Abdala

Dutschmann

Bissonnette

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

159

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Rett syndrome (RTT) is an autism spectrum disorder caused by mutations in the X-linked gene that encodes the transcription factor methyl-CpG-binding protein 2 (MeCP2). A major debilitating phenotype in affected females is frequent apneas, and heterozygous Mecp2-deficient female mice mimic the human respiratory disorder. GABA defects have been demonstrated in the brainstem of Mecp2-deficient mice. Here, using an intact respiratory network, we show that apnea in RTT mice is characterized by excessive excitatory activity in expiratory cranial and spinal nerves. Augmenting GABA markedly improves the respiratory phenotype. In addition, a serotonin 1a receptor agonist that depresses expiratory neuron activity also reduces apnea, corrects the irregular breathing pattern, and prolongs survival in MeCP2 null males. Combining a GABA reuptake blocker with a serotonin 1a agonist in heterozygous females completely corrects their respiratory defects. The results indicate that GABA and serotonin 1a receptor activity are candidates for treatment of the respiratory disorders in Rett syndrome.R ett syndrome (RTT) is an autism spectrum disorder that is caused by mutations in the X-linked gene that encodes methyl-CpG-binding protein 2 (MeCP2) (1). The role of this transcription factor is incompletely understood. Until recently, on the basis of animal studies primarily in embryonic or early neonatal brain, Mecp2 was considered a translational repressor (2, 3). Recently, however, Skene et al. (4) found in neuronal nuclei of mature (6-8 wk) WT littermates of Mecp2 null males that Mecp2 expression is ≈fivefold greater than that at birth. The amount of Mecp2 bound to DNA was proportional to the methylation density of CpG sequences. Importantly, in adult mice, it has been shown that restoring Mecp2 reverses the abnormalities in mobility, gait, hind limb clasping, tremor, breathing, and general condition that they developed during the period that the transcription factor was deficient (5). Thus, Mecp2 deficiency does not cause neuronal degeneration, nor is it necessary for the correct development of neuronal networks. Strategies aimed at pharmacological corrections of symptoms are therefore essential in treating RTT.Respiratory disorders are prominent and one of the most disturbing features of RTT (6, 7). These abnormalities are faithfully mimicked in mouse models of RTT (8). In Mecp2 null male animals studied in situ phrenic (PN) apneas were characterized by prolonged postinspiratory (post-I) activity in the central vagus nerve (9). Post-I activity is linked to the control of laryngeal adductors that control expiratory airflow and protect the lower airways from aspiration during swallowing. Active breath-hold with laryngeal closure is a common feature of RTT (6,7,10).This raises the possibility that the apneas are due to overactive brainstem expiratory neurons in Mecp2 heterozygote mice, perhaps consequent to a lack of synaptic inhibitory control. In this regard, examination of GABA synaptic inhibition in the ventrolateral medulla of Mec...

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Section: Mechanism Of Serotonin 1a Agonist Induced Inhibition Of Expimentioning

confidence: 99%

mentioning

confidence: 99%

Correction of respiratory disorders in a mouse model of Rett syndrome

Abdala

Dutschmann

Bissonnette

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

159

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“…The noradrenergic A7 cell group also overlaps with the KF. In addition to GABA, glycine, and noradrenalin receptors, various glutamate (AMPA/kainic acid, NMDA, and metabotropic receptors (59, 149–152) and cholinergic and serotonergic (5-HT) receptors are expressed in the PB and KF nuclei (103, 165, 244). Moreover, large subset of neuropeptide transmitters such as neurotensin, cholecystokinin, substance P, somatostatin, and calcitonin gene-related peptide and their associated receptors are also expressed (324–327).…”

Section: The Parabrachial Complex and Kölliker-fuse Nuclei Of The Dormentioning

confidence: 99%

Pontine Mechanisms of Respiratory Control

Dutschmann

Dick

2012

Comprehensive Physiology

227

201

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Pontine respiratory nuclei provide synaptic input to medullary rhythmogenic circuits to shape and adapt the breathing pattern. An understanding of this statement depends on appreciating breathing as a behavior, rather than a stereotypic rhythm. In this review, we focus on the pontine-mediated inspiratory off-switch (IOS) associated with postinspiratory glottal constriction. Further, IOS is examined in the context of pontine regulation of glottal resistance in response to multimodal sensory inputs and higher commands, which in turn rules timing, duration, and patterning of respiratory airflow. In addition, network plasticity in respiratory control emerges during the development of the pons. Synaptic plasticity is required for dynamic and efficient modulation of the expiratory breathing pattern to cope with rapid changes from eupneic to adaptive breathing linked to exploratory (foraging and sniffing) and expulsive (vocalizing, coughing, sneezing, and retching) behaviors, as well as conveyance of basic emotions. The speed and complexity of changes in the breathing pattern of behaving animals implies that “learning to breathe” is necessary to adjust to changing internal and external states to maintain homeostasis and survival.

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“…Recent evidence provided by Diethelm Richter’s group suggest that 5-HT 4 R or 5-HT 1A R mediated recovery of μ-opioid receptor evoked respiratory depression or even total arrest (Manzke et al 2003, 2009). The use of a 5-HT 1A R agonist has been shown to evoke breathing recovery following opioid induced respiratory depression in awake rodents (Dutschmann et al, 2009). However it needs to be mentioned that preliminary test in humans failed to produce similar beneficial effect on opioid evoked respiratory depression (Lötsch et al, 2005; Oertel et al, 2007).…”

Section: Therapeutic Use Of Serotonergic Drugs In Central Respiratmentioning

confidence: 99%

The role of serotonin in respiratory function and dysfunction

Hilaire¹,

Voituron²,

Menuet³

et al. 2010

Respiratory Physiology & Neurobiology

145

121

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Serotonin (5-HT) is a neuro-modulator-transmitter influencing global brain function. Past and present findings illustrate a prominent role for 5-HT in the modulation of ponto-medullary autonomic circuits. 5-HT is also involved in the control of neurotrophic processes during pre-and postnatal development of neural circuits. The functional implications of 5-HT is particularly illustrated in the alterations to the serotonergic system, as seen in a wide range of neurological disorders. This article reviews the role of 5-HT in the development and control of respiratory networks in the ponto-medullary brainstem. The review further examines the role of 5-HT in breathing disorders occurring at different stages of life, in particular, the neonatal neurodevelopmental diseases such as Rett, sudden infant death and Prader-Willi syndromes, adult diseases such as sleep apnoea and mental illness linked to neurodegeneration.

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The potency of different serotonergic agonists in counteracting opioid evoked cardiorespiratory disturbances

Cited by 41 publications

References 55 publications

Correction of respiratory disorders in a mouse model of Rett syndrome

Correction of respiratory disorders in a mouse model of Rett syndrome

Pontine Mechanisms of Respiratory Control

The role of serotonin in respiratory function and dysfunction

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