Expression and Function of Serotonin 2A and 2B Receptors in the Mammalian Respiratory Network

Niebert, Marcus; Vogelgesang, Steffen; Koch, Uwe; Bischoff, Anne M.; Kron, Miriam; Bock, Nathalie; Manzke, Till

doi:10.1371/journal.pone.0021395

Cited by 36 publications

(30 citation statements)

References 55 publications

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“…DBA/1 mice express reduced 5-HT 2B/2C and 5-HT 3B receptors in the brainstem [37]. Among these receptors, the 5-HT 2B receptor exerts a stronger excitatory effect than other receptors on respiration [38]. Furthermore, a polymorphism (C1473G) of tryptophan hydroxylase-2 (TPH2), the key enzyme for synthesis of 5-HT in the brain, is found in DBA mice [39].…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

Zeng¹,

Long²,

Cotten³

et al. 2015

Epilepsy & Behavior

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Sudden unexpected death in epilepsy (SUDEP) is a fatal epileptic event. The DBA/1 mouse is a relevant animal model for study of SUDEP, as these mice exhibit seizure-induced respiratory arrest (S-IRA) leading to death, which has been observed in witnessed SUDEP patients. Fluoxetine, a selective serotonin (5-hydroxytryptamine or 5-HT) reuptake inhibitor (SSRI), reduces S-IRA in DBA/1 mice. Given that DBA/1 mice with S-IRA can be resuscitated using a ventilator, we hypothesized that breathing stimulants can prevent S-IRA and that fluoxetine prevents S-IRA by enhancing ventilation in these mice. Spontaneous respiratory function in anesthetized or awake DBA/1 mice was examined using non-invasive plethysmography before and after administering fluoxetine or breathing stimulants, doxapram and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (PK-THPP). The effects of these drugs on S-IRA in DBA/1 mice were tested. As reported previously, systemic administration of fluoxetine reduced S-IRA in awake DBA/1 mice, but fluoxetine in anesthetized and awake DBA/1 mice did not increase basal ventilation or the ventilatory response to 7% CO2. Both doxapram and PK-THPP increased ventilation in room air and in air + 7% CO2 in anesthetized DBA/1 mice. However, neither of the breathing stimulants reduced the incidence of S-IRA. Our studies confirm that fluoxetine reduces S-IRA in DBA/1 mice, but without enhancing basal ventilation in the absence of seizures. Although breathing stimulants increased ventilation in the absence of seizures, they were ineffective in reducing S-IRA, indicating that drug-induced increases in ventilation are insufficient to compensate for S-IRA in DBA/1 mice.

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Section: Discussionmentioning

confidence: 99%

Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

Zeng¹,

Long²,

Cotten³

et al. 2015

Epilepsy & Behavior

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“…The 5-HT system is involved in respiratory drive and chemoreception (Dekin et al, 1985, Richerson, 1995, Wang et al, 1998, Wang and Richerson, 1999, Wang et al, 2001, Pena and Ramirez, 2002, Feldman et al, 2003, Nattie et al, 2004, Hodges and Richerson, 2008a, Hodges et al, 2008, Li and Nattie, 2008, Corcoran et al, 2009, Hodges et al, 2009, Ptak et al, 2009, Hodges and Richerson, 2010, Niebert et al, 2011, Ray et al, 2011). Nevertheless, we did not observe any significant change in breathing in normoxia, hypercapnia or hypoxia between male or female mice after deletion of 5-HT neurons with systemic administration of DT.…”

Section: Discussionmentioning

confidence: 99%

Diphtheria toxin treatment of Pet-1-Cre floxed diphtheria toxin receptor mice disrupts thermoregulation without affecting respiratory chemoreception

Cerpa¹,

Gonzalez²,

Richerson³

2014

Neuroscience

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In genetically-modified Lmx1bf/f/p mice, selective deletion of LMX1B in Pet-1 expressing cells leads to failure of embryonic development of serotonin (5-HT) neurons. As adults, these mice have a decreased hypercapnic ventilatory response and abnormal thermoregulation. This mouse model has been valuable in defining the normal role of 5-HT neurons, but it is possible that developmental compensation reduces the severity of observed deficits. Here we studied mice genetically modified to express diphtheria toxin receptors (DTR) on Pet-1 expressing neurons (Pet-1-Cre/Floxed DTR or Pet1/DTR mice). These mice developed with a normal complement of 5-HT neurons. As adults, systemic treatment with 2 – 35 μg diphtheria toxin (DT) reduced the number of tryptophan hydroxylase immunoreactive (TpOH-ir) neurons in the raphe nuclei and ventrolateral medulla by 80%. There were no effects of DT on baseline ventilation (VE) or the ventilatory response to hypercapnia or hypoxia. At an ambient temperature (TA) of 24°C, all Pet1/DTR mice dropped their body temperature (TB) below 35°C after DT treatment, but the latency was shorter in males than females (3.0 ± 0.37 vs 4.57 ± 0.29 days, respectively; p < 0.001). One week after DT treatment, mice were challenged by dropping TA from 37°C to 24°C, which caused TB to decrease more in males than in females (29.7 ± 0.31°C vs 33.0 ± 1.3°C, p < 0.01). We conclude that the 20% of 5-HT neurons that remain after DT treatment in Pet1/DTR mice are sufficient to maintain normal baseline breathing and a normal response to CO2, while those affected include some essential for thermoregulation, in males more than females. In comparison to models with deficient embryonic development of 5-HT neurons, acute deletion of 5-HT neurons in adults leads to a greater defect in thermoregulation, suggesting that significant developmental compensation can occur.

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“…A deficit in serotonin could lead to inactivation of inspiration-terminating neurons, which could manifest as an increase in inspiratory time and a reduction in breathing frequency-evident in our Tph2 −/− mice and other mouse models (i.e., Lmx1b f/f/p ). On the other hand, since 5-HT 2B and 5-HT 2A receptor activation stimulates breathing frequency (37), the binding of serotonin to inspiration-terminating neurons, expressing serotonin excitatory receptors, also appears to contribute to increases in breathing frequency (42).…”

Section: Baseline Measures Before Intermittent Hypoxiamentioning

confidence: 99%

Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin

Hickner

Hussain

Angoa‐Pérez

et al. 2014

Journal of Applied Physiology

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Our study was designed to determine if central nervous system (CNS) serotonin is required for the induction of ventilatory long-term facilitation (LTF) in intact, spontaneously breathing mice. Nineteen tryptophan hydroxylase 2-deficient (Tph2(-/-)) mice, devoid of serotonin in the CNS, and their wild-type counterparts (Tph2(+/+)) were exposed to intermittent hypoxia each day for 10 consecutive days. The ventilatory response to intermittent hypoxia was greater in the Tph2(+/+) compared with the Tph2(-/-) mice (1.10 ± 0.10 vs. 0.77 ± 0.01 ml min(-1)·percent(-1) oxygen; P ≤ 0.04). Ventilatory LTF, caused by increases in breathing frequency, was evident in Tph2(+/+) and Tph2(-/-) mice following exposure to intermittent hypoxia each day; however, the magnitude of the response was greater in the Tph2(+/+) compared with the Tph2(-/-) mice (1.11 ± 0.02 vs. 1.05 ± 0.01 normalized to baseline on each day; P ≤ 0.01). The magnitude of ventilatory LTF increased significantly from the initial to the finals days of the protocol in the Tph2(-/-) (1.06 ± 0.02 vs. 1.11 ± 0.03 normalized to baseline on the initial days; P ≤ 0.004) but not in the Tph2(+/+) mice. This enhanced response was mediated by increases in tidal volume. Body temperature and metabolic rate did not account for differences in the magnitude of ventilatory LTF observed between groups after acute and repeated daily exposure to intermittent hypoxia. We conclude that ventilatory LTF, after acute exposure to intermittent hypoxia, is mediated by increases in breathing frequency and occurs in the absence of serotonin, although the magnitude of the response is diminished. This weakened response is enhanced following repeated daily exposure to intermittent hypoxia, via increases in tidal volume, to a similar magnitude evident in Tph2(+/+) mice. Thus the magnitude of ventilatory LTF following repeated daily exposure to intermittent hypoxia is not dependent on the presence of CNS serotonin.

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Expression and Function of Serotonin 2A and 2B Receptors in the Mammalian Respiratory Network

Cited by 36 publications

References 55 publications

Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

Fluoxetine prevents respiratory arrest without enhancing ventilation in DBA/1 mice

Diphtheria toxin treatment of Pet-1-Cre floxed diphtheria toxin receptor mice disrupts thermoregulation without affecting respiratory chemoreception

Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin

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