alpha CaMKII controls the establishment of cocaine's reinforcing effects in mice and humans

alpha CaMKII controls the establishment of cocaine's reinforcing effects in mice and humans

Author Easton, A. C. Google Scholar
Lourdusamy, A. Google Scholar
Havranek, M. Google Scholar
Mizuno, K. Google Scholar
Solati, J. Google Scholar
Golub, Y. Google Scholar
Clarke, T-K Google Scholar
Vallada, Homero Google Scholar
Laranjeira, Ronaldo Autor UNIFESP Google Scholar
Desrivieres, S. Google Scholar
Moll, G. H. Google Scholar
Moessner, R. Google Scholar
Kornhuber, J. Google Scholar
Schumann, G. Google Scholar
Giese, K. P. Google Scholar
Fernandes, C. Google Scholar
Quednow, B. B. Google Scholar
Mueller, C. P. Google Scholar
Institution Kings Coll London
Univ Nottingham
Univ Zurich
Univ Clin Erlangen
Islamic Azad Univ
Univ Penn
Universidade de São Paulo (USP)
Universidade Federal de São Paulo (UNIFESP)
Univ Bonn
Univ Erlangen Nurnberg
Abstract Although addiction develops in a considerable number of regular cocaine users, molecular risk factors for cocaine dependence are still unknown. It was proposed that establishing drug use and memory formation might share molecular and anatomical pathways. Alpha-Ca2+/calmodulin-dependent protein kinase-II (alpha CaMKII) is a key mediator of learning and memory also involved in drug-related plasticity. the autophosphorylation of aCaMKII was shown to accelerate learning. Thus, we investigated the role of aCaMKII autophosphorylation in the time course of establishing cocaine use-related behavior in mice. We found that alpha CaMKII autophosphorylation-deficient alpha CaMKIIT286A mice show delayed establishment of conditioned place preference, but no changes in acute behavioral activation, sensitization or conditioned hyperlocomotion to cocaine (20 mg kg(-1), intraperitoneal). in vivo microdialysis revealed that alpha CaMKIIT286A mice have blunted dopamine (DA) and blocked serotonin (5-HT) responses in the nucleus accumbens (NAcc) and prefrontal cortex after acute cocaine administration (20 mg kg(-1), intraperitoneal), whereas noradrenaline responses were preserved. Under cocaine, the attenuated DA and 5-HT activation in alpha CaMKIIT286A mice was followed by impaired c-Fos activation in the NAcc. To translate the rodent findings to human conditions, several CAMK2A gene polymorphisms were tested regarding their risk for a fast establishment of cocaine dependence in two independent samples of regular cocaine users from Brazil (n = 688) and Switzerland (n = 141). A meta-analysis across both samples confirmed that CAMK2A rs3776823 TT-allele carriers display a faster transition to severe cocaine use than C-allele carriers. Together, these data suggest that alpha CaMKII controls the speed for the establishment of cocaine's reinforcing effects.
Language English
Sponsor Institute of Psychiatry, King's College London
Friedrich-Alexander-University of Erlangen-Nuremberg
Medical Research Council, UK
European Union
FP7 project IMAGEMEND (IMAging GEnetics for MENtal Disorders)
Innovative Medicine Initiative Project EU-AIMS
Medical Research Council
Swedish funding agency FORMAS
Bundesministerium fur Bildung und Forschung (BMBF)
Swiss National Science Foundation (SNSF)
Olga Mayenfisch Foundation
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Grant number European Union: LSHM-CT-2007-037286
Innovative Medicine Initiative Project EU-AIMS: 115300-2
Medical Research Council: 93558
Bundesministerium fur Bildung und Forschung (BMBF): 01EV0711
Swiss National Science Foundation (SNSF): PP00P1-123516/1
Swiss National Science Foundation (SNSF): PP00P1-146326/1
Date 2014-10-01
Published in Translational Psychiatry. New York: Nature Publishing Group, v. 4, 9 p., 2014.
ISSN 2158-3188 (Sherpa/Romeo, impact factor)
Publisher Nature Publishing Group
Extent 9
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000344827100002

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