title: αCaMKII autophosphorylation controls the establishment of alcohol drinking behavior.
abstract: The α-Ca(2+)/calmodulin-dependent protein kinase II (αCaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of αCaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of αCaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in αCaMKII autophosphorylation-deficient αCaMKII(T286A) mice, but could be established at wild-type level after repeated withdrawals. The locomotor activating effects of a low-dose alcohol (2 g/kg) were absent in αCaMKII(T286A) mice, whereas the sedating effects of high-dose (3.5 g/kg) were preserved after acute and subchronic administration. The in vivo microdialysis revealed that αCaMKII(T286A) mice showed no dopamine (DA) response in the nucleus accumbens to acute or subchronic alcohol administration, but enhanced serotonin (5-HT) responses in the prefrontal cortex. The attenuated DA response in αCaMKII(T286A) mice was in line with altered c-Fos activation in the ventral tegmental area after acute and subchronic alcohol administration. In order to compare findings in mice with the human condition, we tested 23 single-nucleotide polymorphisms (SNPs) in the CAMK2A gene for their association with alcohol dependence in a population of 1333 male patients with severe alcohol dependence and 939 controls. We found seven significant associations between CAMK2A SNPs and alcohol dependence, one of which in an autophosphorylation-related area of the gene. Together, our data suggest αCaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.
authors: MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, London, UK.
authors: Alanna C
authors: AC
authors: Easton
authors: Walter
authors: W
authors: Lucchesi
authors: Anbarasu
authors: A
authors: Lourdusamy
authors: Bernd
authors: B
authors: Lenz
authors: Jalal
authors: J
authors: Solati
authors: Yulia
authors: Y
authors: Golub
authors: Piotr
authors: P
authors: Lewczuk
authors: Cathy
authors: C
authors: Fernandes
authors: Sylvane
authors: S
authors: Desrivieres
authors: Ralph R
authors: RR
authors: Dawirs
authors: Gunther H
authors: GH
authors: Moll
authors: Johannes
authors: J
authors: Kornhuber
authors: Josef
authors: J
authors: Frank
authors: Per
authors: P
authors: Hoffmann
authors: Michael
authors: M
authors: Soyka
authors: Falk
authors: F
authors: Kiefer
authors: Gunter
authors: G
authors: Schumann
authors: K
authors: K
authors: Peter Giese
authors: Christian P
authors: CP
authors: Müller
authors: Jens
authors: J
authors: Treutlein
authors: Sven
authors: S
authors: Cichon
authors: Monika
authors: M
authors: Ridinger
authors: Peter
authors: P
authors: Mattheisen
authors: Stefan
authors: S
authors: Herms
authors: Norbert
authors: N
authors: Wodarz
authors: Peter
authors: P
authors: Zill
authors: Wolfgang
authors: W
authors: Maier
authors: Rainald
authors: R
authors: Mössner
authors: Wolfgang
authors: W
authors: Gaebel
authors: Norbert
authors: N
authors: Dahmen
authors: Norbert
authors: N
authors: Scherbaum
authors: Christine
authors: C
authors: Schmäl
authors: Michael
authors: M
authors: Steffens
authors: Susanne
authors: S
authors: Lucae
authors: Marcus
authors: M
authors: Ising
authors: Bertram
authors: B
authors: Müller-Myhsok
authors: Markus M
authors: MM
authors: Nöthen
authors: Karl
authors: K
authors: Mann
authors: Marcella
authors: M
authors: Rietschel
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000437:Alcoholism / Q000235:genetics*; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
chemical_list: D006993:Hypnotics and Sedatives; D012701:Serotonin; D000431:Ethanol; C517657:CAMK2A protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; D004298:Dopamine