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.
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.
Parlato
Rosanna
R
Department of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany. r.parlato@dkfz.de
Cruz
Hans
H
Otto
Christiane
C
Murtra
Patricia
P
Parkitna
Jan Rodriguez
JR
Martin
Miquel
M
Bura
Simona A
SA
Begus-Nahrmann
Yvonne
Y
von Bohlen und Halbach
Oliver
O
Maldonado
Rafael
R
Schütz
Günther
G
Lüscher
Christian
C
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
D017362:Cyclic AMP Response Element-Binding Protein; D009294:Narcotics; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D009020:Morphine; D009638:Norepinephrine