The role of 5-HT3 and other excitatory receptors in central cardiorespiratory responses to hypoxia: implications for sudden infant death syndrome.
Although brainstem serotonergic (5-HT) systems are involved in the protective responses to hypoxia, abnormalities of 5-HT function are strongly implicated in SIDS, and the neurochemical mechanisms by which 5-HT receptors influence brainstem cardiorespiratory responses to hypoxia remains unclear. This study focuses on the role of excitatory neurotransmission, including 5-HT3 signaling, to cardiac vagal neurons (CVNs) that dominate the control of heart rate. Excitatory synaptic inputs to CVNs, located in the nucleus ambiguus (NA), were recorded simultaneously with respiratory activity in in vitro brainstem slices. During control conditions excitatory inputs to CVNs were blocked by application of NMDA and AMPA/kainate glutamatergic receptor antagonists, whereas the 5-HT3 and purinergic receptor antagonists ondansetron and pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), respectively, had no effect. However, during hypoxia ondansetron inhibited excitatory neurotransmission to CVNs. In recovery from hypoxia, spontaneous and respiratory-related excitatory events were blocked by glutamatergic and purinergic receptor blockers, respectively, whereas ondancetron had no effect. These results demonstrate that hypoxia recruits a 5-HT pathway to CVNs that activates 5-HT3 receptors on CVNs to maintain parasympathetic cardiac activity during hypoxia. Exaggeration of this 5-HT neurotransmission could increase the incidence of bradycardia and risk of sudden infant death during hypoxia.
Dergacheva
Olga
O
Department of Pharmacology and Physiology, The George Washington University, Washington, DC 20037, USA. olgad@gwu.edu
Kamendi
Harriet
H
Wang
Xin
X
Pinol
Ramon Manchon
RM
Frank
Julie
J
Jameson
Heather
H
Gorini
Christopher
C
Mendelowitz
David
D
D000818:Animals; D001933:Brain Stem / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007223:Infant; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D013398:Sudden Infant Death; D014630:Vagus Nerve / Q000166:cytology / Q000502:physiology
D017470:Receptors, Glutamate; D011983:Receptors, Purinergic; D044406:Receptors, Serotonin, 5-HT3; D012701:Serotonin