State-dependent interactions between excitatory neuromodulators in the neuronal control of breathing

J Neurosci. 2010 Jun 16;30(24):8251-62. doi: 10.1523/JNEUROSCI.5361-09.2010.


All neuronal networks are modulated by multiple neuropeptides and biogenic amines. Yet, few studies investigate how different modulators interact to regulate network activity. Here we explored the state-dependent functional interactions between three excitatory neuromodulators acting on neurokinin1 (NK1), alpha1 noradrenergic (alpha1 NE), and 5-HT2 serotonin receptors within the pre-Bötzinger complex (pre-BötC), an area critical for the generation of breathing. In anesthetized, in vivo mice, the reliance on endogenous NK1 activation depended on spontaneous breathing frequency and the modulatory state of the animal. Endogenous NK1 activation had no significant respiratory effect when stimulating raphe magnus and/or locus ceruleus, but became critical when alpha1 NE and 5-HT2 receptors were pharmacologically blocked. The dependence of the centrally generated respiratory rhythm on NK1 activation was blunted in the presence of alpha1 NE and 5-HT2 agonists as demonstrated in slices containing the pre-BötC. We conclude that a modulator's action is determined by the concurrent modulation and interaction with other neuromodulators. Deficiencies in one neuromodulator are immediately compensated by the action of other neuromodulators. This interplay could play a role in the state dependency of certain breathing disorders.

Publication types

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

MeSH terms

  • Action Potentials / drug effects
  • Adrenergic alpha-1 Receptor Antagonists
  • Animals
  • Animals, Newborn
  • Electric Stimulation / methods
  • Electromyography / methods
  • Hypoglossal Nerve / physiology
  • In Vitro Techniques
  • Isoindoles / pharmacology
  • Ketanserin / pharmacology
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / physiology
  • Mice
  • Microinjections / methods
  • Neural Inhibition / drug effects
  • Neural Pathways / physiology
  • Neurokinin-1 Receptor Antagonists
  • Neurons / drug effects*
  • Neurons / physiology
  • Neurotransmitter Agents / pharmacology*
  • Piperidines / pharmacology
  • Raphe Nuclei / drug effects
  • Raphe Nuclei / physiology
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Neurokinin-1 / metabolism
  • Receptors, Serotonin, 5-HT2 / metabolism
  • Respiration*
  • Respiratory Center / cytology*
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists / pharmacology


  • Adrenergic alpha-1 Receptor Antagonists
  • Isoindoles
  • Neurokinin-1 Receptor Antagonists
  • Neurotransmitter Agents
  • Piperidines
  • Receptors, Adrenergic, alpha-1
  • Receptors, Neurokinin-1
  • Receptors, Serotonin, 5-HT2
  • Serotonin 5-HT2 Receptor Antagonists
  • Serotonin Antagonists
  • 7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one
  • 3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine
  • Ketanserin