Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine

Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine

Autor Bilbao, Ainhoa Google Scholar
Parkitna, Jan Rodriguez Google Scholar
Engblom, David Google Scholar
Perreau-Lenz, Stephanie Google Scholar
Sanchis-Segura, Carles Google Scholar
Schneider, Miriam Google Scholar
Konopka, Witold Google Scholar
Westphal, Magdalena Google Scholar
Breen, Gerome Google Scholar
Desrivieres, Sylvane Google Scholar
Klugmann, Matthias Google Scholar
Guindalini, Camila Autor UNIFESP Google Scholar
Vallada, Homero Google Scholar
Laranjeira, Ronaldo Autor UNIFESP Google Scholar
Fonseca, Fernando Rodriguez de Google Scholar
Schumann, Gunter Google Scholar
Schuetz, Guenther Google Scholar
Spanagel, Rainer Google Scholar
Instituição 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
Resumo 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.
Palavra-chave addiction
CaMKIV
CREB
striatum
Idioma Inglês
Financiador National Genome Research Network plus
Deutsche Forschungsgemeinschaft
United Kingdom Department of Health National Institute for Health Research
Biomedical Research Centre for Mental Health at Institute of Psychiatry (King's College London)
Ramon y Cajal program (Minisiterio de Educacion y Ciencia, Spain)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Institute of Health Carlos III Red RTA
Plan Nacional Sobre Drogas y Proyectos de Excelencia de la Consejeria de Innovacion
Department of Neurobiology, University of Heidelberg
Alexander von Humboldt Foundation (Wolfgang-Paul-Prize to Hilmar Bading)
European Molecular Biology Organization
Número do financiamento National Genome Research Network plus: AZ: 01GS08152
Deutsche Forschungsgemeinschaft: SFB636
Institute of Health Carlos III Red RTA: G06/001
Data de publicação 2008-11-11
Publicado em 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.
ISSN 0027-8424 (Sherpa/Romeo, fator de impacto)
Publicador Natl Acad Sciences
Extensão 17549-17554
Fonte http://dx.doi.org/10.1073/pnas.0803959105
Direito de acesso Acesso aberto Open Access
Tipo Artigo
Web of Science WOS:000260981800070
Endereço permanente http://repositorio.unifesp.br/handle/11600/31034

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