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

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.National Genome Research Network plusDeutsche ForschungsgemeinschaftUnited Kingdom Department of Health National Institute for Health ResearchBiomedical 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 RTAPlan Nacional Sobre Drogas y Proyectos de Excelencia de la Consejeria de InnovacionDepartment of Neurobiology, University of HeidelbergAlexander von Humboldt Foundation (Wolfgang-Paul-Prize to Hilmar Bading)European Molecular Biology OrganizationGerman Canc Res Ctr, D-69120 Heidelberg, GermanyCent Inst Mental Hlth, Dept Psychopharmacol, D-68159 Mannheim, GermanyKings Coll London, Inst Psychiat, Interdisciplinary Res Grp Addict, London SE5 8AF, EnglandJohannes Gutenberg Univ Mainz, Dept Physiol Chem, D-55099 Mainz, GermanyUniversidade Federal de São Paulo, Dept Psychiat, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04023900 São Paulo, BrazilUniv São Paulo, Dept Psychiat, BR-01060970 São Paulo, BrazilHosp Carlos Haya, Mediterranean Inst Adv Biotechnol & Hlth Res, Malaga 29010, SpainUniversidade Federal de São Paulo, Dept Psychiat, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Psychobiol, BR-04023900 São Paulo, BrazilNational Genome Research Network plus: AZ: 01GS08152Deutsche Forschungsgemeinschaft: SFB636Institute of Health Carlos III Red RTA: G06/001Web of Scienc