RGD Reference Report - Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine. - Rat Genome Database

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

Authors: Bilbao, Ainhoa  Parkitna, Jan Rodriguez  Engblom, David  Perreau-Lenz, Stéphanie  Sanchis-Segura, Carles  Schneider, Miriam  Konopka, Witold  Westphal, Magdalena  Breen, Gerome  Desrivieres, Sylvane  Klugmann, Matthias  Guindalini, Camila  Vallada, Homero  Laranjeira, Ronaldo  de Fonseca, Fernando Rodriguez  Schumann, Gunter  Schütz, Günther  Spanagel, Rainer 
Citation: Bilbao A, etal., Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17549-54. doi: 10.1073/pnas.0803959105. Epub 2008 Nov 10.
RGD ID: 401938643
Pubmed: PMID:19001277   (View Abstract at PubMed)
PMCID: PMC2582267   (View Article at PubMed Central)
DOI: DOI:10.1073/pnas.0803959105   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CAMK4Humancocaine dependence no_associationIAGP DNA:SNPs: :rs1457115 and rs9285875RGD 
CAMK4Humancocaine dependence  IAGP DNA:SNP: :rs919334RGD 
CREB1Humancocaine dependence no_associationIAGP DNA:SNPs: :rs10876469 and rs2177000RGD 
Camk4Ratcocaine dependence no_associationISOCAMK4 (Homo sapiens)DNA:SNPs: :rs1457115 and rs9285875RGD 
Camk4Mousecocaine dependence  ISOCAMK4 (Homo sapiens)DNA:SNP: :rs919334RGD 
Camk4Mousecocaine dependence no_associationISOCAMK4 (Homo sapiens)DNA:SNPs: :rs1457115 and rs9285875RGD 
Camk4Ratcocaine dependence  ISOCAMK4 (Homo sapiens)DNA:SNP: :rs919334RGD 
Creb1Ratcocaine dependence no_associationISOCREB1 (Homo sapiens)DNA:SNPs: :rs10876469 and rs2177000RGD 
Creb1Mousecocaine dependence no_associationISOCREB1 (Homo sapiens)DNA:SNPs: :rs10876469 and rs2177000RGD 

Objects Annotated

Genes (Rattus norvegicus)
Camk4  (calcium/calmodulin-dependent protein kinase IV)
Creb1  (cAMP responsive element binding protein 1)

Genes (Mus musculus)
Camk4  (calcium/calmodulin-dependent protein kinase IV)
Creb1  (cAMP responsive element binding protein 1)

Genes (Homo sapiens)
CAMK4  (calcium/calmodulin dependent protein kinase IV)
CREB1  (cAMP responsive element binding protein 1)


Additional Information