Stimulation of the rat medullary raphe nuclei induces differential responses in respiratory muscle activity.

Neural control circuits that coordinate the motor activity of the diaphragm (DIA) and the geniohyoid muscle (GH) are potentially involved in pathological conditions such as various forms of sleep apnea. Here we investigated a differential role of the raphe magnus (RMg), pallidus (RPa) and the obscurus (ROb) nuclei in the neural control of DIA and GH muscle activity in rats under volatile anesthesia. In order to characterize a topographical organization of the raphe nuclei we analyzed changes in DIA and GH during high-frequency stimulation (HFS, 10-130 Hz, 60 micros pulse width, 40-160 microA, 30s). HFS of the RMg and the ROb induced apnea, in the latter case apnea was associated with massive tonic discharge in the GH. By contrast, HFS of the RPa induced tachypnea. At caudal stimulation sites the tachypnea was accompanied by tonic DIA activity and cessation of GH. These data suggest a differential distribution of inhibitory and excitatory drives of DIA and GH muscles within distinct raphe nuclei.

Time- and dose-related effects of three 5-HT receptor ligands on the genioglossus activity in anesthetized and conscious rats.

Clinical trials in obstructive sleep apnea syndrome patients reported moderate effects of serotoninergic drugs on oropharyngeal apneas, although numerous specific 5-HT ligands highly modulate the genioglossus muscle (GG) activity in experiments performed in anesthetized animals. The purpose of this study was to investigate time- and dose-related effects of central and systemic injections of 8-OHDPAT (5-HT1A agonist), SB224289 (5-HT1B antagonist), and DOI (5-HT2A/2C agonist) on the GG activity in anesthetized and conscious rats. Electromyographic recordings of the GG activity (GGemg) were analyzed after central and systemic injections of each drug in ketamine-xylazine anesthetized rats. Electroencephalograms (EEG), as well as neck and GG muscle activities (Nemg and GGemg), were recorded in 15 additional rats to analyze changes in sleep-wake states before and after systemic injection of the drugs. Central injections of 8-OHDPAT and DOI in anesthetized rats induced clear dose-related increases in phasic and tonic GGemg activities, respectively. The time-responses were inferior to 30 min with 8-OHDPAT and over 50 min with DOI. Moderate increases in phasic GGemg activity were also observed after central, but not peripheral injection of SB and DOI. The total sleep time measured in conscious rats significantly decreased after systemic injections of DOI and 8-OHDPAT, although no change was observed in phasic or tonic GGemg activity. The dose- and time-responses of the DOI in anesthetized rat partly explain the lack of GGemg tonic change in conscious rat. The moderate effect on the GGemg phasic activity of peripheral 5-HT1A ligand injection easily explains the lack of change in conscious rat. The serotonergic modulation of the respiratory component of the GGemg remains complex, but is highly sensitive to 5-HT1A receptors after central injection in rats under anesthesia. Forthcoming therapy in OSAS should be made of mixed profiled neurotransmitters and different routes of administration.