Essential role of the cAMP-cAMP response-element binding protein pathway in opiate-induced homeostatic adaptations of locus coeruleus neurons

Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):17011-6. doi: 10.1073/pnas.1010077107. Epub 2010 Sep 13.


Excessive inhibition of brain neurons in primary or slice cultures can induce homeostatic intrinsic plasticity, but the functional role and underlying molecular mechanisms of such plasticity are poorly understood. Here, we developed an ex vivo locus coeruleus (LC) slice culture system and successfully recapitulated the opiate-induced homeostatic adaptation in electrical activity of LC neurons seen in vivo. We investigated the mechanisms underlying this adaptation in LC slice cultures by use of viral-mediated gene transfer and genetic mutant mice. We found that short-term morphine treatment of slice cultures almost completely abolished the firing of LC neurons, whereas chronic morphine treatment increased LC neuronal excitability as revealed during withdrawal. This increased excitability was mediated by direct activation of opioid receptors and up-regulation of the cAMP pathway and accompanied by increased cAMP response-element binding protein (CREB) activity. Overexpression of a dominant negative CREB mutant blocked the increase in LC excitability induced by morphine- or cAMP-pathway activation. Knockdown of CREB in slice cultures from floxed CREB mice similarly decreased LC excitability. Furthermore, the ability of morphine or CREB overexpression to up-regulate LC firing was blocked by knockout of the CREB target adenylyl cyclase 8. Together, these findings provide direct evidence that prolonged exposure to morphine induces homeostatic plasticity intrinsic to LC neurons, involving up-regulation of the cAMP-CREB signaling pathway, which then enhances LC neuronal excitability.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptation, Physiological / drug effects
  • Adenylyl Cyclases / genetics
  • Animals
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Gene Knockout Techniques
  • Homeostasis / drug effects
  • Locus Coeruleus / drug effects*
  • Locus Coeruleus / metabolism
  • Locus Coeruleus / physiology
  • Mice
  • Mice, Transgenic
  • Morphine / pharmacology*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / physiology
  • Rats
  • Rats, Sprague-Dawley


  • Cyclic AMP Response Element-Binding Protein
  • Morphine
  • Cyclic AMP
  • Adenylyl Cyclases
  • adenylyl cyclase 8