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

doi:10.1073/pnas.0803959105

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

^aDepartment of Psychopharmacology, Central Institute of Mental Health, J5, 68159 Mannheim, Germany;
^bMolecular Biology of the Cell I, German Cancer Research Center, 69120 Heidelberg, Germany;
^cInterdisciplinary Research Group Addiction, Institute of Psychiatry at King's College London, London SE5 8AF, United Kingdom;
^dDepartment of Physiological Chemistry, University of Mainz, D-55099 Mainz, Germany;
^eDepartment of Psychiatry, Universidade Federal de São Paulo, 04023-900 São Paulo, Brazil;
^fDepartment of Psychobiology, Universidade Federal de São Paulo, 04023-900 São Paulo, Brazil;
^gDepartment of Psychiatry, Universidade de São Paulo, 01060-970 São Paulo, Brazil; and
^hThe Mediterranean Institute for the Advance of Biotechnology and Health Research, Hospital Carlos Haya, 29010 Málaga, Spain

Edited by George F. Koob, The Scripps Research Institute, La Jolla, CA, and accepted by the Editorial Board September 12, 2008
↵¹A.B. and J.R.P. contributed equally. (received for review April 24, 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.

Footnotes

²To whom correspondence should be addressed. E-mail: j.rodriguez{at}dkfz-heidelberg.de
Author contributions: A.B., J.R.P., D.E., G.B., H.V., R.L., F.R.D.F., G. Schumann, G. Schütz, and R.S. designed research; A.B., J.R.P., D.E., S.P.-L., C.S.-S., M.S., W.K., M.W., S.D., M.K., and C.G. performed research; A.B., J.R.P., D.E., M.S., G.B., M.K., and R.S. analyzed data; and A.B., J.R.P., G. Schütz, and R.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. G.F.K. is a guest editor invited by the Editorial Board.
Data deposition: Gene expression profiling data have been deposited with the Gene Expression Omnibus (GSE10869).
This article contains supporting information online at www.pnas.org/cgi/content/full/0803959105/DCSupplemental.