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

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.Institute of Psychiatry, King's College LondonFriedrich-Alexander-University of Erlangen-NurembergMedical Research Council, UKEuropean UnionFP7 project IMAGEMEND (IMAging GEnetics for MENtal Disorders)Innovative Medicine Initiative Project EU-AIMSMedical Research CouncilSwedish funding agency FORMASBundesministerium fur Bildung und Forschung (BMBF)Swiss National Science Foundation (SNSF)Olga Mayenfisch FoundationFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Res Ctr, MRC, London, EnglandUniv Nottingham, Sch Med, Fac Med & Hlth Sci, Nottingham, EnglandUniv Zurich, Hosp Psychiat, Dept Psychiat Psychotherapy & Psychosomat, Zurich, SwitzerlandKings Coll London, Inst Psychiat, Ctr Cellular Basis Behav, London, EnglandUniv Clin Erlangen, Dept Child & Adolescent Mental Hlth, Erlangen, GermanyIslamic Azad Univ, Fac Sci, Dept Biol, Karaj Branch, Karaj, IranUniv Penn, Sch Med, Dept Psychiat, Translat Res Lab, Philadelphia, PA 19104 USAUniv São Paulo, Sch Med, Dept & Inst Psychiat, São Paulo, BrazilUniversidade Federal de São Paulo, UNIAD, São Paulo, BrazilUniv Bonn, Dept Psychiat, Bonn, GermanyUniv Erlangen Nurnberg, Univ Hosp, Dept Psychiat & Psychotherapy, D-91054 Erlangen, GermanyUniversidade Federal de São Paulo, UNIAD, São Paulo, BrazilEuropean Union: LSHM-CT-2007-037286Innovative Medicine Initiative Project EU-AIMS: 115300-2Medical Research Council: 93558Bundesministerium fur Bildung und Forschung (BMBF): 01EV0711Swiss National Science Foundation (SNSF): PP00P1-123516/1Swiss National Science Foundation (SNSF): PP00P1-146326/1Web of Scienc