In vitro characterization of noradrenergic modulation of chemosensitive neurons in the retrotrapezoid nucleus

J Neurophysiol. 2016 Sep 1;116(3):1024-35. doi: 10.1152/jn.00022.2016. Epub 2016 Jun 15.


Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to CO2/H(+) changes and serve as an integration center for other autonomic centers, including brain stem noradrenergic neurons. Norepinephrine (NE) contributes to respiratory control and chemoreception, and, since disruption of NE signaling may contribute to several breathing disorders, we sought to characterize effects of NE on RTN chemoreception. All neurons included in this study responded similarly to CO2/H(+) but showed differential sensitivity to NE; we found that NE activated (79%), inhibited (7%), or had no effect on activity (14%) of RTN chemoreceptors. The excitatory effect of NE on RTN chemoreceptors was dose dependent, retained in the presence of neurotransmitter receptor blockers, and could be mimicked and blocked by pharmacological manipulation of α1-adrenergic receptors (ARs). In addition, NE-activation was blunted by XE991 (KCNQ channel blocker), and partially occluded the firing response to serotonin, suggesting involvement of KCNQ channels. However, in whole cell voltage clamp, activation of α1-ARs decreased outward current and conductance by what appears to be a mixed effect on multiple channels. The inhibitory effect of NE on RTN chemoreceptors was blunted by an α2-AR antagonist. A third group of RTN chemoreceptors was insensitive to NE. We also found that chemosensitive RTN astrocytes do not respond to NE with a change in voltage or by releasing ATP to enhance activity of chemosensitive neurons. These results indicate NE modulates subsets of RTN chemoreceptors by mechanisms involving α1- and α2-ARs.

Keywords: KCNQ channels; adrenergic receptors; chemoreception; neonatal brain slice; norepinephrine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects*
  • Adrenergic Agents / pharmacology
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects
  • Carbon Dioxide / pharmacology
  • Chemoreceptor Cells / drug effects*
  • Chemoreceptor Cells / physiology*
  • Dose-Response Relationship, Drug
  • In Vitro Techniques
  • Neurotransmitter Agents / pharmacology
  • Norepinephrine / metabolism*
  • Norepinephrine / pharmacology
  • Patch-Clamp Techniques
  • Rats
  • Receptors, Adrenergic / metabolism*
  • Respiratory Center / cytology*
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology


  • Adrenergic Agents
  • Neurotransmitter Agents
  • Receptors, Adrenergic
  • Sodium Channel Blockers
  • Carbon Dioxide
  • Tetrodotoxin
  • Norepinephrine