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

Article Article scientifique Article 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 eng 2010 author Parlato Rosanna author Cruz Hans 104837 author Otto Christiane author Murtra Patricia author Parkitna Jan Rodriguez author Martin Miquel author Bura Simona A author Begus-Nahrmann Yvonne author von Bohlen und Halbach Oliver author Maldonado Rafael author Schütz Günther author Luescher Christian 132337 563-573 10.1111/j.1471-4159.2010.06709.x 20367754 0022-3042 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. 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 Dewey 616.8 53 Département de neurosciences fondamentales 21A false 271 Mécanismes cellulaires de la dépendance et de l'addiction 520 Journal of neurochemistry 115 3 52870fe5-2c28-477a-b040-448ef5482859 Article (Published version) Restricted HCJNeurochemistry2010.pdf 886588 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales

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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	Journal of neurochemistry			2010	535	0

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Cruz, Hans