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

Central Institute of Mental Health, Mannheim German Cancer Research Center, Heidelberg German Cancer Research Center, Heidelberg Central Institute of Mental Health, Mannheim Central Institute of Mental Health, Mannheim Central Institute of Mental Health, Mannheim German Cancer Research Center, Heidelberg German Cancer Research Center, Heidelberg King's College London King's College London University of Mainz Universidade Federal de São Paulo Universidade de São Paulo Universidade Federal de São Paulo Hospital Carlos Haya King's College London Central Institute of Mental Health, Mannheim Central Institute of Mental Health, J5, 68159 Mannheim National Academy of Sciences; 1999 2008

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.

addiction; CaMKIV; CREB; striatum; Medical and Health Sciences; Medicin och hälsovetenskap; Article in journal; info:eu-repo/semantics/article; text

10.1073.pnas.0803959105

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info:eu-repo/semantics/restrictedAccess

English

UPE oai:DiVA.org:liu-59697
0000-0001-6501-9077
doi:10.1073/pnas.0803959105
ISI:000260981800070
1234289596

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