Developmental nicotine exposure alters cholinergic control of respiratory frequency in neonatal rats

Dev Neurobiol. 2016 Oct;76(10):1138-49. doi: 10.1002/dneu.22380. Epub 2016 Feb 17.


Prenatal nicotine exposure with continued exposure through breast milk over the first week of life (developmental nicotine exposure, DNE) alters the development of brainstem circuits that control breathing. Here, we test the hypothesis that DNE alters the respiratory motor response to endogenous and exogenous acetylcholine (ACh) in neonatal rats. We used the brainstem-spinal cord preparation in the split-bath configuration, and applied drugs to the brainstem compartment while measuring the burst frequency and amplitude of the fourth cervical ventral nerve roots (C4VR), which contain the axons of phrenic motoneurons. We applied ACh alone; the nicotinic acetylcholine receptor (nAChR) antagonist curare, either alone or in the presence of ACh; and the muscarinic acetylcholine receptor (mAChR) antagonist atropine, either alone or in the presence of ACh. The main findings include: (1) atropine reduced frequency similarly in controls and DNE animals, while curare caused modest slowing in controls but no consistent change in DNE animals; (2) DNE greatly attenuated the increase in C4VR frequency mediated by exogenous ACh; (3) stimulation of nAChRs with ACh in the presence of atropine increased frequency markedly in controls, but not DNE animals; (4) stimulation of mAChRs with ACh in the presence of curare caused a modest increase in frequency, with no treatment group differences. DNE blunts the response of the respiratory central pattern generator to exogenous ACh, consistent with reduced availability of functionally competent nAChRs; DNE did not alter the muscarinic control of respiratory motor output. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1138-1149, 2016.

Keywords: acetylcholine; brainstem-spinal cord preparation; cholinergic; control of breathing; muscarinic receptor; nicotinic receptor.

Publication types

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

MeSH terms

  • Acetylcholine / metabolism*
  • Acetylcholine / pharmacology
  • Animals
  • Animals, Newborn
  • Atropine / pharmacology
  • Brain Stem / drug effects
  • Brain Stem / growth & development
  • Brain Stem / metabolism
  • Cholinergic Agonists / pharmacology
  • Curare / pharmacology
  • Disease Models, Animal
  • Female
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Muscarinic Antagonists / pharmacology
  • Nicotine / toxicity*
  • Nicotinic Agonists / toxicity*
  • Nicotinic Antagonists / pharmacology
  • Phrenic Nerve / drug effects
  • Phrenic Nerve / growth & development
  • Phrenic Nerve / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Rats, Sprague-Dawley
  • Respiration* / drug effects
  • Spinal Cord / drug effects
  • Spinal Cord / growth & development
  • Spinal Cord / metabolism
  • Tissue Culture Techniques


  • Cholinergic Agonists
  • Muscarinic Antagonists
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Nicotine
  • Atropine
  • Curare
  • Acetylcholine