5-HT2A receptor activation is necessary for CO2-induced arousal.
Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT(2A) receptors dose-dependently blocked CO2-induced arousal. The 5-HT(2C) receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1b(f/f/p)) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT(2A), but not 5-HT(2C), receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT(2A) receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system.
Department of Neurology, Yale University, New Haven, Connecticut; Veteran's Affairs Medical Center, West Haven, Connecticut; Department of Neurology, University of Iowa, Iowa City, Iowa; gordon-buchanan@uiowa.edu.
Gordon F
GF
Buchanan
Department of Neurology, Yale University, New Haven, Connecticut;
Haleigh R
HR
Smith
University of Glasgow School of Medicine, Glasgow, Scotland, United Kingdom;
Amanda
A
MacAskill
Department of Neurology, Yale University, New Haven, Connecticut; Department of Neurology, University of Iowa, Iowa City, Iowa; Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa; and Veteran's Affairs Medical Center, Iowa City, Iowa.
George B
GB
Richerson
D000818:Animals; D001143:Arousal / Q000187:drug effects / Q000502:physiology*; D002245:Carbon Dioxide / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004576:Electromyography; D006935:Hypercapnia / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010991:Plethysmography; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D013686:Telemetry; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D018377:Neurotransmitter Agents; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D014157:Transcription Factors; D044282:Receptor, Serotonin, 5-HT1A; D002245:Carbon Dioxide
CO2; Lmx1b; arousal; hypercapnia; mouse; serotonin; sleep