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Title

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

Authors
Parlato, Rosanna
Otto, Christiane
Murtra, Patricia
Parkitna, Jan Rodriguez
Martin, Miquel
Bura, Simona A
Begus-Nahrmann, Yvonne
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Published in Journal of Neurochemistry. 2010, vol. 115, no. 3, p. 563-73
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 AnimalsBrain/anatomy & histologyCell Survival/geneticsChromatography, High Pressure LiquidChronic DiseaseCyclic AMP Response Element Modulator/genetics/physiologyCyclic AMP Response Element-Binding Protein/genetics/physiologyElectrochemistryElectrophysiologyFemaleGenotypeIn Situ HybridizationLocus Coeruleus/cytology/physiologyMaleMiceMice, KnockoutMorphine/adverse effectsMorphine Dependence/physiopathology/psychologyNarcotics/adverse effectsNorepinephrine/physiologySubstance Withdrawal Syndrome/physiopathology/psychologySympathetic Nervous System/cytology/physiologyTranscription Factors/physiology
Identifiers
PMID: 20367754
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Research group Mécanismes cellulaires de la dépendance et de l'addiction (520)
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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. 563-73. https://archive-ouverte.unige.ch/unige:26930

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Deposited on : 2013-03-25

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