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Scientific article
English

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

Published inJournal of neurochemistry, vol. 115, no. 3, p. 563-573
Publication date2010
Abstract

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.

Keywords
  • Animals
  • Brain/anatomy & histology
  • Cell Survival/genetics
  • Chromatography, High Pressure Liquid
  • Chronic Disease
  • Cyclic AMP Response Element Modulator/genetics/physiology
  • Cyclic AMP Response Element-Binding Protein/genetics/physiology
  • Electrochemistry
  • Electrophysiology
  • Female
  • Genotype
  • In Situ Hybridization
  • Locus Coeruleus/cytology/physiology
  • Male
  • Mice
  • Mice, Knockout
  • Morphine/adverse effects
  • Morphine Dependence/physiopathology/psychology
  • Narcotics/adverse effects
  • Norepinephrine/physiology
  • Substance Withdrawal Syndrome/physiopathology/psychology
  • Sympathetic Nervous System/cytology/physiology
  • Transcription Factors/physiology
Citation (ISO format)
PARLATO, Rosanna et al. 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. In: Journal of neurochemistry, 2010, vol. 115, n° 3, p. 563–573. doi: 10.1111/j.1471-4159.2010.06709.x
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Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal0022-3042
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