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Title: Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine
Authors: Bilbao, Ainhoa
Parkitna, Jan Rodriguez
Engblom, David
Perreau-Lenz, Stephanie
Sanchis-Segura, Carles
Schneider, Miriam
Konopka, Witold
Westphal, Magdalena
Breen, Gerome
Desrivieres, Sylvane
Klugmann, Matthias
Guindalini, Camila [UNIFESP]
Vallada, Homero
Laranjeira, Ronaldo [UNIFESP]
Fonseca, Fernando Rodriguez de
Schumann, Gunter
Schuetz, Guenther
Spanagel, Rainer
German Canc Res Ctr
Cent Inst Mental Hlth
Kings Coll London
Johannes Gutenberg Univ Mainz
Universidade Federal de São Paulo (UNIFESP)
Universidade de São Paulo (USP)
Hosp Carlos Haya
Keywords: addiction
Issue Date: 11-Nov-2008
Publisher: Natl Acad Sciences
Citation: Proceedings of the National Academy of Sciences of the United States of America. Washington: Natl Acad Sciences, v. 105, n. 45, p. 17549-17554, 2008.
Abstract: The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.
ISSN: 0027-8424
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