Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia

Proc Natl Acad Sci U S A. 2014 Mar 11;111(10):3859-64. doi: 10.1073/pnas.1310025111. Epub 2014 Feb 24.


Mechanisms driving emergence from general anesthesia are not well understood. The noradrenergic brain nucleus locus coeruleus (LC) modulates arousal and may have effects on general anesthetic state. Using virally delivered designer receptors to specifically control LC norepinephrine (NE) neurons, we investigated the causal relationship between LC-NE activity and general anesthetic state under isoflurane. Selective activation of LC-NE neurons produced cortical electroencephalography (EEG) activation under continuous deep isoflurane anesthesia. Specifically, LC-NE activation reduced burst suppression in EEG and drove a rightward shift in peak EEG frequency with reduced δ EEG power and increased θ EEG power, measures of cortical arousal. LC-NE activation also accelerated behavioral emergence from deep isoflurane anesthesia; this was prevented with β or α1 noradrenergic antagonists. Moreover, these adrenoreceptor antagonists alone were sufficient to markedly potentiate anesthetic duration when delivered centrally or peripherally. Induction of anesthesia also was retarded by LC-NE activation. Our results demonstrate that the LC-NE system strongly modulates the anesthetic state, and that changes in LC-NE neurotransmission alone can affect the emergence from isoflurane general anesthesia. Taken together, these findings extend our understanding of mechanisms underlying general anesthesia and cortical arousal, and have significant implications for optimizing the clinical safety and management of general anesthesia.

Keywords: DREADD; RASSL.

Publication types

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

MeSH terms

  • Adrenergic Neurons / physiology*
  • Anesthesia Recovery Period*
  • Anesthesia, General / methods*
  • Animals
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Electroencephalography
  • Isoflurane / metabolism*
  • Locomotion / drug effects
  • Locus Coeruleus / physiology*
  • Luminescent Proteins
  • Norepinephrine / antagonists & inhibitors
  • Norepinephrine / metabolism*
  • Rats
  • Rats, Long-Evans


  • Luminescent Proteins
  • red fluorescent protein
  • Isoflurane
  • Clozapine
  • clozapine N-oxide
  • Norepinephrine