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 Ca(2+)/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.
Bilbao
Ainhoa
A
Department of Psychopharmacology, Central Institute of Mental Health, J5, 68159 Mannheim, Germany.
Parkitna
Jan Rodriguez
JR
Engblom
David
D
Perreau-Lenz
Stéphanie
S
Sanchis-Segura
Carles
C
Schneider
Miriam
M
Konopka
Witold
W
Westphal
Magdalena
M
Breen
Gerome
G
Desrivieres
Sylvane
S
Klugmann
Matthias
M
Guindalini
Camila
C
Vallada
Homero
H
Laranjeira
Ronaldo
R
de Fonseca
Fernando Rodriguez
FR
Schumann
Gunter
G
Schütz
Günther
G
Spanagel
Rainer
R
D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D001938:Brazil; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics*; D019970:Cocaine-Related Disorders / Q000235:genetics* / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse