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?CaMKII autophosphorylation controls the establishment of alcohol drinking behavior.

ABSTRACT: The ?-Ca(2+)/calmodulin-dependent protein kinase II (?CaMKII) is a crucial enzyme controlling plasticity in the brain. The autophosphorylation of ?CaMKII works as a 'molecular memory' for a transient calcium activation, thereby accelerating learning. We investigated the role of ?CaMKII autophosphorylation in the establishment of alcohol drinking as an addiction-related behavior in mice. We found that alcohol drinking was initially diminished in ?CaMKII autophosphorylation-deficient ?CaMKII(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 ?CaMKII(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 ?CaMKII(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 ?CaMKII(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 ?CaMKII autophosphorylation as a facilitating mechanism in the establishment of alcohol drinking behavior with changing the DA-5-HT balance as a putative mechanism.

SUBMITTER: Easton AC

PROVIDER: S-EPMC3717547 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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αCaMKII autophosphorylation controls the establishment of alcohol drinking behavior.

Easton Alanna C AC Lucchesi Walter W Lourdusamy Anbarasu A Lenz Bernd B Solati Jalal J Golub Yulia Y Lewczuk Piotr P Fernandes Cathy C Desrivieres Sylvane S Dawirs Ralph R RR Moll Gunther H GH Kornhuber Johannes J Frank Josef J Hoffmann Per P Soyka Michael M Kiefer Falk F Schumann Gunter G Peter Giese K K Müller Christian P CP Treutlein Jens J Cichon Sven S Ridinger Monika M Mattheisen Peter P Herms Stefan S Wodarz Norbert N Zill Peter P Maier Wolfgang W Mössner Rainald R Gaebel Wolfgang W Dahmen Norbert N Scherbaum Norbert N Schmäl Christine C Steffens Michael M Lucae Susanne S Ising Marcus M Müller-Myhsok Bertram B Nöthen Markus M MM Mann Karl K Rietschel Marcella M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20130304 9

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 ...[more]

PMID: 23459588

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?CaMKII autophosphorylation controls the establishment of alcohol drinking behavior.

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αCaMKII autophosphorylation controls the establishment of alcohol drinking behavior.

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