Effects of the cell type-specific ablation of the cAMP-responsive transcription factor in noradrenergic neurons on locus coeruleus firing and withdrawal behavior after chronic exposure to morphine

J Neurochem. 2010 Nov;115(3):563-73. doi: 10.1111/j.1471-4159.2010.06709.x. Epub 2010 Aug 19.


Repeated exposure to opiates leads to cellular and molecular changes and behavioral alterations reflecting a state of dependence. In noradrenergic neurons, cyclic AMP (cAMP)-dependent pathways are activated during opiate withdrawal, but their contribution to the activity of locus coeruleus noradrenergic neurons and behavioral manifestations remains controversial. Here, we test whether the cAMP-dependent transcription factors cAMP responsive element binding protein (CREB) and cAMP-responsive element modulator (CREM) in noradrenergic neurons control the cellular markers and the physical signs of morphine withdrawal in mice. Using the Cre/loxP system we ablated the Creb1 gene in noradrenergic neurons. To avoid adaptive effects because of compensatory up-regulation of CREM, we crossed the conditional Creb1 mutant mice with a Crem-/- line. We found that the enhanced expression of tyrosine hydroxylase normally observed during withdrawal was attenuated in CREB/CREM mutants. Moreover, the withdrawal-associated cellular hyperactivity and c-fos expression was blunted. In contrast, naloxone-precipitated withdrawal signs, such as jumping, paw tremor, tremor and mastication were preserved. We conclude by a specific genetic approach that the withdrawal-associated hyperexcitability of noradrenergic neurons depends on CREB/CREM activity in these neurons, but does not mediate several behavioral signs of morphine withdrawal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / anatomy & histology
  • Cell Survival / genetics
  • Chromatography, High Pressure Liquid
  • Chronic Disease
  • Cyclic AMP Response Element Modulator / genetics*
  • Cyclic AMP Response Element Modulator / physiology*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / physiology*
  • Electrochemistry
  • Electrophysiology
  • Female
  • Genotype
  • In Situ Hybridization
  • Locus Coeruleus / cytology
  • Locus Coeruleus / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Morphine / adverse effects
  • Morphine Dependence / physiopathology
  • Morphine Dependence / psychology*
  • Narcotics / adverse effects
  • Norepinephrine / physiology*
  • Substance Withdrawal Syndrome / physiopathology
  • Substance Withdrawal Syndrome / psychology*
  • Sympathetic Nervous System / cytology
  • Sympathetic Nervous System / physiology*
  • Transcription Factors / physiology


  • Cyclic AMP Response Element-Binding Protein
  • Narcotics
  • Transcription Factors
  • Cyclic AMP Response Element Modulator
  • Morphine
  • Norepinephrine