Activation of alpha-2 noradrenergic receptors is critical for the generation of fictive eupnea and fictive gasping inspiratory activities in mammals in vitro

Eur J Neurosci. 2011 Jun;33(12):2228-37. doi: 10.1111/j.1460-9568.2011.07706.x. Epub 2011 May 25.

Abstract

Biogenic amines are not just 'modulators', they are often essential for the execution of behaviors. Here, we explored the role of biogenic amines acting on the pre-Bötzinger complex (pre-BötC), an area located in the ventrolateral medulla which is critical for the generation of different forms of breathing. Isolated in transverse slices from mice, this region continues to spontaneously generate rhythmic activities that resemble normal (eupneic) inspiratory activity in normoxia and gasping in hypoxia. We refer to these as 'fictive eupneic' and 'fictive gasping' activity. When exposed to hypoxia, the pre-BötC transitions from a network state relying on calcium-activated nonspecific cation currents (I(CAN)) and persistent sodium currents (I(Nap)) to one that primarily depends on the I(Nap) current. Here we show that in inspiratory neurons I(Nap)-dependent bursting, blocked by riluzole, but not I(CAN) -dependent bursting, required endogenously released norepinephrine acting on alpha2-noradrenergic receptors (α2-NR). At the network level, fictive eupneic activity persisted while fictive gasping ceased following the blockade of α2-NR. Blockade of α2-NR eliminated fictive gasping even in slice preparations as well as in inspiratory island preparations. Blockade of fictive gasping by α2-NR antagonists was prevented by activation of 5-hydroxytryptamine type 2A receptors (5-HT2A). Our data suggest that gasping depends on the converging aminergic activation of 5-HT2AR and α2-NR acting on riluzole-sensitive mechanisms that have been shown to be crucial for gasping.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adrenergic alpha-2 Receptor Antagonists / pharmacology
  • Animals
  • Animals, Outbred Strains
  • Biological Clocks / drug effects
  • Biological Clocks / physiology*
  • Hypoxia / physiopathology
  • In Vitro Techniques
  • Mice
  • Patch-Clamp Techniques
  • Receptor, Serotonin, 5-HT2A / physiology
  • Receptors, Adrenergic, alpha-2 / physiology*
  • Respiratory Center / drug effects
  • Respiratory Center / physiology*
  • Respiratory Mechanics / drug effects
  • Respiratory Mechanics / physiology*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology

Substances

  • Adrenergic alpha-2 Receptor Antagonists
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-2
  • Serotonin 5-HT2 Receptor Agonists