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 plus[AZ: 01GS08152]

Deutsche Forschungsgemeinschaft (DFG)[SFB636]

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)

CAPES Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

Institute of Health Carlos III Red RTA[G06/001]

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