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.
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.
authors.affiliation: Department of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany. r.parlato@dkfz.de
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parlato
authors.forename: Hans
authors.initials: H
authors.lastname: Cruz
authors.forename: Christiane
authors.initials: C
authors.lastname: Otto
authors.forename: Patricia
authors.initials: P
authors.lastname: Murtra
authors.forename: Jan Rodriguez
authors.initials: JR
authors.lastname: Parkitna
authors.forename: Miquel
authors.initials: M
authors.lastname: Martin
authors.forename: Simona A
authors.initials: SA
authors.lastname: Bura
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Begus-Nahrmann
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen und Halbach
authors.forename: Rafael
authors.initials: R
authors.lastname: Maldonado
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Christian
authors.initials: C
authors.lastname: Lüscher
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology; D002470:Cell Survival / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics* / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000502:physiology*; D004563:Electrochemistry; D004594:Electrophysiology; D005260:Female; D005838:Genotype; D017403:In Situ Hybridization; D008125:Locus Coeruleus / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects; D009021:Morphine Dependence / Q000503:physiopathology / Q000523:psychology*; D009294:Narcotics / Q000009:adverse effects; D009638:Norepinephrine / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000523:psychology*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009294:Narcotics; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D009020:Morphine; D009638:Norepinephrine