8-OH-DPAT suppresses spontaneous central apneas in the C57BL/6J mouse strain

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Respiratory Physiology & Neurobiology 161 (2008) 10–15

8-OH-DPAT suppresses spontaneous central apneasin the C57BL/6J mouse strain

Georg M. Stettner a,∗,1, Sebastien Zanella b,1, Gerard Hilaire b, Mathias Dutschmann c,d

a Department of Pediatrics and Pediatric Neurology, University Medicine Gottingen,Georg August University, Robert-Koch-Str. 40, 37075 Gottingen, Germany

b CNRS UMR 6153, MP3-Respiration (Maturation, Plasticity, Physiology and Pathology of Respiration),Faculte Saint Jerome, 13397 Marseille Cedex 20, France

c Department of Neuro and Sensory Physiology, University Medicine Gottingen, Georg August University,Humboldtallee 23, 37073 Gottingen, Germany

d DFG Research Center Molecular Physiology of the Brain (CMPB), Humboldtallee 23, 37073 Gottingen, Germany

Accepted 8 November 2007

bstract

Apneas are common and prognostically relevant disorders of the central control of breathing, but pharmacological interventions are dissatisfying.he respiratory phenotype of C57BL/6J mice is characterized by the occurrence of spontaneous central apneas with laryngeal closure. In the presenttudy we investigated the impact of the 5-HT1A receptor agonist 8-OH-DPAT on apneas in C57BL/6J mice, because of the important role of serotoninn the regulation of breathing and previous reports showing that serotonergic drugs can affect central apneas. Whole-body plethysmography inwake, unrestrained mice revealed that intraperitoneal application of 8-OH-DPAT (10 �g kg−1) decreased the occurrence of spontaneous apneas

rom 1.91 ± 0.25 to 1.05 ± 0.05 apneas min−1. The efficacy of 5-HT1A receptor activation was further verified in the in situ working heart–brainstemreparation. Here the apneas occurred at a frequency of 1.33 ± 0.19 min−1. Intra-arterial perfusion with 1–2 �M 8-OH-DPAT completely abolishedpontaneous apneas. These results suggest that 5-HT1A receptor activation may be a potential treatment option for central apneas.

2007 Elsevier B.V. All rights reserved.

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eywords: Neuronal control of breathing; Spontaneous central apnea; Upper a

. Introduction

Experimental therapeutic studies of spontaneous apneas werereferentially undertaken in adult rats as a model for centralleep apneas (Mendelson et al., 1988; Sato et al., 1990). Most ofhese studies focused on the serotonergic system since serotonin

5-hydroxytryptamine (5-HT)] influences a wide range of physi-logical systems including the regulation of breathing. In partic-lar, effects of 5-HT3 antagonists as well as drugs with a mixed-

Abbreviations: 5-HT, 5-hydroxytryptamine; 8-OH-DPAT, (R)-(+)-8-ydroxy-2-(di-n-propylamino)tetralin hydrobromide; AI, apnea index (apneasin−1); cVN, central vagal nerve; f, respiratory frequency (cycles min−1); i.p.,

ntraperitoneal; n.s., not significant; OSAS, obstructive sleep apnea syndrome;N, phrenic nerve; PNA, phrenic nerve activity (bursts min−1); Ttot, total respi-atory cycle duration (s); WHBP, working heart–brainstem preparation.∗ Corresponding author. Tel.: +49 551 39 2570; fax: +49 551 39 6252.

E-mail address: [email protected] (G.M. Stettner).1 These authors contributed equally to this work.

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control; OSAS; Apnea of prematurity; Serotonin

rofile of activation and/or inhibition of different 5-HT receptorubtypes were extensively studied (Radulovacki et al., 1998;arley and Radulovacki, 1999; Carley et al., 2001). In addition,-HT1A receptor agonists were effectively used for the treatmentf respiratory disturbances such as apneusis (Lalley et al., 1994)nd apneas of different origin in various species (Sahibzada etl., 2000; Choi et al., 2005). The impact of 5-HT1A receptorctivation on spontaneous apneas, however, was not yet studied.

In a recent study we found that spontaneous centralpneas occur in the C57BL/6J mouse strain (Stettner etl., 2008). Thus, this mouse strain is a useful model fornvestigating neuronal mechanisms leading to apneas and forvaluating therapeutic approaches. The aim of this study waso analyze the impact of 8-OH-DPAT [(R)-(+)-8-hydroxy-2-di-n-propylamino)tetralin hydrobromide], a selective 5-HT1A

eceptor agonist, on the expression of spontaneous apneas in57BL/6J mice. In accordance with our previous study (Stettnert al., 2008) spontaneous apneas occurred in awake, unanes-hetized C57BL/6J mice as well as in the in situ working

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G.M. Stettner et al. / Respiratory Phy

eart–brainstem preparation (WHBP). Intraperitoneal applica-ion of 8-OH-DPAT (10 �g kg−1) in awake mice decreased therequency of apneas. In the in situ WHBP apneas were abolishedy systemic application of 1 �M 8-OH-DPAT.

. Materials and methods

The experimental procedures were performed according tohe European Community and National Institutes of Healthuidelines for the care and use of laboratory animals. Thetudy was approved by the ethics committee of the University

edicine Gottingen and the Centre National de la Recherchecientifique Marseille. All C57BL/6J mice used for this studyere at adult age (postnatal day 40–60).

.1. Plethysmographic recording of in vivo breathingatterns

In full accordance with the experimental procedures ofur previous study (Stettner et al., 2008) breathing wasecorded from eight unrestrained awake C57BL/6J mice using ahole-body flow plethysmograph (EMKA Technologies, Paris,rance). Only those recording periods were analyzed duringhich the animals were quiet (i.e. without major limb, body

nd head movements) albeit obviously awake, as assessed byehavioral observation by the investigator. The entire recordingeriod was at least 2 h. We used periods of quiet wakefulnessf about 30 min to measure the total respiratory cycle durationTtot, expressed in s) for each cycle and to calculate the meanespiratory frequency (f; expressed in cycles min−1). We definedn apnea as a respiratory arrest for a period of at least two res-iratory cycles based on the mean Ttot and an apnea index (AI)s the number of apneas per min.

.1.1. Experimental protocol for the pharmacological studyn vivo

The animals were randomly pooled into two groups (each= 4) to measure the impact of two different doses of-OH-DPAT (10 �g kg−1 and 1 mg kg−1; (R)-(+)-8-hydroxy--(di-n-propylamino)tetralin hydrobromide; catalog number:080; Tocris, Ellisville, USA) on spontaneous apneas. 8-OH-PAT was dissolved in saline 0.9 % to a total volume of 0.2 mler intraperitoneal (i.p.) injection.

All mice were habituated to the plethysmograph for two hoursnd at the following day control data were recorded. At theubsequent days breathing activities were investigated following.p. injection of 0.2 ml saline 0.9% and 8-OH-DPAT. In all casesata acquisition started no earlier than 30 min after i.p. injection.

.2. Respiratory motor recordings of in situ breathingatterns using the WHBP

The experiments were performed using the arterially perfused

HBP of 14 C57BL/6J mice in full accordance with our pre-

ious study (Stettner et al., 2008). Respiratory motor activitiesf the phrenic (PN) and central vagal nerve (cVN) were simul-aneously recorded. The respiratory parameters were calculated

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y & Neurobiology 161 (2008) 10–15 11

rom 60 consecutive breathing cycles. Breathing frequency wasndicated by the phrenic nerve activity (PNA; bursts min−1). Inddition, frequency and duration of spontaneous apneas over aeriod of at least 5 min was measured. We defined an apnea ashe absence of rhythmic PNA for a period of at least two respi-atory cycles based on the mean Ttot and an AI as the number ofpneas per min. All parameters were analyzed at representative,teady-state activity of each preparation prior and 3 min afterpplication of 8-OH-DPAT.

.2.1. Experimental protocol for the pharmacological studyn situ

We applied 8-OH-DPAT [(R)-(+)-8-hydroxy-2-(di-n-ropylamino)tetralin hydrobromide; catalog number: 1080,ocris, Ellisville, USA] systemically in the in situ preparationy adding it to the perfusate. The concentration of 8-OH-DPATas progressively increased every 10 min (1, 2, 5 and 10 �M)

n 10 preparations. To verify the long-term efficacy of lowose 8-OH-DPAT, we performed recordings for at least 60 minfter drug application of 1 �M 8-OH-DPAT in four additionalreparations.

.3. Statistical analysis

Results are presented as mean ± S.E.M. All in vivo valueshowed a normal distribution and differences between con-rol, vehicle injection and drug treatment were detected using

parametric ANOVA and Holm-Sidak post hoc analyses forair wise comparisons. In the in situ experiments differencesetween control and drug treatment (1, 2, 5, 10 �M) for normallyistributed variables (PNA, duration of apneas) were detectedsing a parametric ANOVA and Dunnett’s post hoc analysesor pair wise comparisons to the control group. Because of theack of apneas after application of 1 �M 8-OH-DPAT we deter-

ined differences in AI using a non-parametric ANOVA withruskal–Wallis test including additional pair wise comparisons.p-value p < 0.05 was considered as significant.

. Results

The respiratory phenotype of adult C57BL/6J mice is charac-erized by spontaneous central apneas in vivo and in situ (Stettnert al., 2008). It has been previously shown that 5-HT1A receptorgonists have the potency to stabilize respiratory disturbancesncluding apneas of different origin (Sahibzada et al., 2000; Choit al., 2005). In the present study we analyzed the impact of the-HT1A receptor agonist 8-OH-DPAT on spontaneous centralpneas in C57BL/6J mice.

.1. Impact of 8-OH-DPAT on spontaneous apneas in57BL/6J mice in vivo

Two groups of C57BL/6J mice (each n = 4) were used to

easure the impact of two different doses of 8-OH-DPAT on

pontaneous apneas. Both groups showed no significant differ-nces in their breathing during control conditions, including f, AInd apnea duration (Fig. 1). Vehicle injection (saline 0.9%) also

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12 G.M. Stettner et al. / Respiratory Physiology & Neurobiology 161 (2008) 10–15

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ig. 1. Impact of two different doses (10 �g kg−1 and 1 mg kg−1) of 8-OH-DPbreaths min−1; C) in C57BL/6J mice in vivo (n = 4 for both treatment groups).

ad no significant influence on the baseline breathing activitiesn both groups (Fig. 1).

Intraperitoneal application of 10 �g kg−1 8-OH-DPATignificantly decreased the AI. Compared to controlAI = 1.91 ± 0.25) and vehicle injection (AI = 1.75 ± 0.11),he AI was reduced by 8-OH-DPAT treatment to 1.05 ± 0.05p = 0.017 and p = 0.025; Fig. 1A). The mean apnea dura-ion decreased slightly to 0.96 ± 0.05 s compared to control1.13 ± 0.05 s) and vehicle injection (1.11 ± 0.06 s) (both notignificant (n.s.); Fig. 1B). In contrast, f (cycle min−1) increasedrom 155 ± 8 (control) and 160 ± 6 (vehicle) to 175 ± 4 after-OH-DPAT application (p = 0.02 and p = 0.06; Fig. 1C).

A dose of 1 mg kg−1 8-OH-DPAT led to an increase inI from 1.63 ± 0.25 (control) and 1.70 ± 0.07 (vehicle) to

.08 ± 0.52 (p = 0.008 and p = 0.01; Fig. 1A). The mean apneauration and the mean f did not show statistically significantifferences compared to control activity (Fig. 1B and C).

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ig. 2. Impact of 8-OH-DPAT on apnea index (apneas min−1; A), apnea durations (Bin−1; C) in C57BL/6J in situ preparations (n = 10). 8-OH-DPAT was applied systemean ± S.E.M. ***, p < 0.001.

apnea index (apneas min−1; A), apnea durations (B) and breathing frequencylts are presented as mean ± S.E.M. *, p < 0.05; **, p < 0.01.

.2. Impact of 8-OH-DPAT on spontaneous apneas in57BL/6J in situ

We used 14 adult C57BL/6J mice to investigate the effectf 5-HT1A receptor activation on central apneas in the WHBP.ontrol respiratory motor activity was characterized by a regularnd fast respiratory frequency [101 ± 7 bursts min−1 (Fig. 2C)]s indicated by the PNA and occurrence of spontaneous transientpneas. During control conditions AI was 1.33 ± 0.19 (Fig. 2A).he mean duration of these apneas was 2.59 ± 0.14 s (Fig. 2B),ccounting for a 4.18 ± 0.21-fold increase in the mean Ttot.

In 10/14 C57BL/6J preparations 8-OH-DPAT was appliedystemically with consecutively increasing concentrations of 1,, 5, and 10 �M in a 10 min interval. Apneas were abolished

uring the 10 min intervals of 1 and 2 �M 8-OH-DPAT (both< 0.001; Figs. 2A and 3). At concentrations of 5 and 10 �M-OH-DPAT AI was 0.40 ± 0.13 and 0.36 ± 0.10, respectively,

) and respiratory frequency indicated by the phrenic nerve activity (PNA; burstsically in increasing concentrations (1, 2, 5, 10 �M). Results are presented as

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ig. 3. Application of the 5-HT1A receptor agonist 8-OH-DPAT abolishes spontf integrated phrenic (ʃPNA) and integrated central vagal motor nerve activities1 �M).

nd did not significantly differ from control (Fig. 2A). Our datahow a dose dependent effect of 8-OH-DPAT on central apneasn C57BL/6J in situ preparations. The most favorable result waschieved with 1–2 �M 8-OH-DPAT.

To verify long-term efficacy of low dose 8-OH-DPAT, weerformed recordings for at least 60 min after application of�M 8-OH-DPAT in 4/14 preparations. No apneas reappeareduring the long–term recording period after application of 1 �M-OH-DPAT.

Overall, 8-OH-DPAT had no significant influence on the PNAurst frequency that showed only subtle fluctuations (control,01 ± 7 min−1; 1 �M, 92 ± 10 min−1; 2 �M, 94 ± 12 min−1;�M, 97 ± 12 min−1; 10 �M, 104 ± 11 min−1; all n.s.).

. Discussion

Previously we reported on the occurrence of spontaneousentral apneas with laryngeal closure in the C57BL/6J mousetrain and discussed the value of this mouse strain and the in situ

HBP for investigating the neuronal mechanisms of centralpneas (Stettner et al., 2008). Here we show that intra-arterialpplication of the 5-HT1A receptor agonist 8-OH-DPAT at con-entrations of 1 and 2 �M abolished spontaneous central apneasn situ. These results implicate that 8-OH-DPAT is able to sta-ilize potentially disturbed respiratory brainstem functions of57BL/6J mice under these experimental conditions. Awake,nanesthetized C57BL/6J mice also display spontaneous apneasStettner et al., 2008) and show an inherited predispositionor disordered breathing (Han and Strohl, 2000). Importantly,ntraperitoneal application of 10 �g kg−1 8-OH-DPAT reducedhe AI in awake, unanesthetized C57BL/6J mice. These resultsnderline a potential therapeutic impact of 5-HT1A receptorgonists on central apneas.

.1. Impact of 5-HT1A receptor activation on centralpneas

Serotonin is an important neurotransmitter, which plays a keyole in the control of a large variety of sensory and motor func-ions. Serotonergic neurons are located in the raphe nuclei androject to all regions of the brain and spinal cord, including

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s central apneas in C57BL/6J in situ preparations. The figure shows recordingsA) of a representative preparation before and after application of 8-OH-DPAT

he lower brainstem and the pons that contain essential ele-ents of the respiratory neuronal network (Hilaire and Duron,

999; Richter et al., 2003). Rabies virus tracing experimentsave revealed synaptic connections between raphe neurons andhe medullary respiratory network in both neonatal and adult

ice (Gaytan et al., 2002; Bevengut et al., in press). A mal-unction of the serotonergic system has implications in severaleurological disorders including various forms of respiratoryailures (Erickson et al., 2007). For example, a severe dysregu-ation of the serotonergic system seems to be closely linked tohe sudden infant death syndrome (Paterson et al., 2006). In the

entioned study, particularly the expression of 5-HT1A recep-ors was significantly altered, suggesting that these receptors

ay be of major importance for the stabilization of autonomicunctions. Another disease most likely linked to monoaminergicnd especially serotonergic dysfunctions, is the Rett syndrome.eCP2-deficient mice, an animal model for the Rett syn-

rome, develop a severe and progressive breathing disturbanceharacterized by central apneas (Viemari et al., 2005) and a post-nspiratory dysfunction (Stettner et al., 2007a). In addition, a

arked decrease in the medullary content of endogenous 5-HTas been reported in MeCP2-deficient mice (Ide et al., 2005;iemari et al., 2005).

The 5-HT1A receptor is the most extensively studied sero-onin receptor (Barnes and Sharp, 1999). In neonatal rats and

ice, endogenous 5-HT has been shown to exert a facilitatoryodulation on the respiratory rhythm generator via medullary

-HT1A receptors (Hilaire and Duron, 1999; Bou-Flores et al.,000). The increased breathing frequency reported herein afterpplications of 8-OH-DPAT to awake adult mice is consistentith the persistence of this 5-HT1A facilitation during adult-ood. The precise mechanisms how 5-HT1A agonists decreasehe occurrence of apneas is still unknown and was not inves-igated in the present study. However, it was proposed thatctivation of 5-HT1A receptors leads to a reduced excitabilityf respiratory neurons and stabilizes respiratory dysrhythmiasRichter et al., 2003). Several studies demonstrated that 5-HT1A

eceptor agonists compensate respiratory disturbances such aspneusis (Lalley et al., 1994) and apneas of different origin inifferent species (Sahibzada et al., 2000; Choi et al., 2005).esults of the present study show that 8-OH-DPAT is also

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apable of abolishing spontaneous central apneas with activearyngeal closure without affecting baseline breathing activitiessing an in situ approach. Importantly, central apneas could alsoe alleviated by intraperitoneal application of 8-OH-DPAT inivo.

At high concentrations of 8-OH-DPAT the apneas re-occurredin situ; 10 �M) and were even increased (in vivo; 1 mg kg−1)hen compared to control activity, respectively. This suggests

hat non-selective side effects of 5-HT1A activation or activationf other 5-HT receptor subtypes (e.g. 1B, 2A, 2B, 3, etc.) atigher concentrations have to be taken into consideration.

For clinical application, buspirone, a partial 5-HT1A receptorgonist is available and already broadly used as an anxiolyticrug. Results from investigations in rat demonstrated identicalespiratory responses to 8-OH-DPAT and buspirone (Sahibzadat al., 2000; Teng et al., 2003). Buspirone has further beenffectively used in the treatment of apneustic disturbances inndividual patients (Wilken et al., 1997; Richter et al., 2003;l-Khatib et al., 2003). However, as reviewed in a recentochrane review on drug therapy for obstructive sleep apneayndrome (OSAS) in adults (Smith et al., 2006), buspironeailed to reduce the apnea index significantly in a limited studyith five patients suffering from OSAS (Mendelson et al.,991). This could implicate that buspirone rather affects centralpneas.

Nevertheless, the recognized efficacy of the 5-HT1A recep-or agonist 8-OH-DPAT to alleviate spontaneous centralpneas demonstrated in this study is of significant relevanceor clinical pharmacology. Many neurological diseases thatnclude severe breathing disturbances are untreatable at theresent stage. The results of the present study suggest newrug trials on apnea syndromes using 5-HT1A receptor ago-ists.

ompeting interests

The authors declare that they have no competing interests.

cknowledgements

The authors thank A.M. Bischoff for excellent technical assis-ance, Dr. K. Kohler (Department of Genetic Epidemiology,niversity Medicine Gottingen, Georg August University) for

tatistical advice and Drs. U. Durr and I. Brandes for valuableuggestions on the manuscript. G.M. Stettner and S. Zanellaere supported by Post-Doctoral Fellowship Awards of the Rettyndrome Research Foundation (RSRF Cincinnati/USA). Thetudy was supported by the DFG Research Center for Molec-lar Physiology of the Brain (CMPB Gottingen/Germany), theentre National de la Recherche Scientifique (France) and therench Ministry of Research (ACI NIC 0054).

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