Behavioural Brain Research 252 (2013) 72–76 Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l h o mepa ge: www.elsevier.com/locate/bbr Short communication CaMKII autophosphorylation controls the establishment of alcohol-induced conditioned place preference in mice Alanna C. Easton a , Walter Lucchesi b , Keiko Mizuno b , Cathy Fernandes a , Gunter Schumann a , K. Peter Giese b , Christian P. Müller a,c,∗ a MRC Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF, UK b Centre for the Cellular Basis of Behavior, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London, James Black Centre, 125 Coldharbour Lane, London SE5 8AF, UK c Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany h i g h l i g h t s • Autophosphorylation of CaMKII is important for drug memory formation. • CaMKII autophosphorylation plays a role in the development of alcohol CPP. • CaMKII autophosphorylation deficient mice show accelerated CPP. • Alcohol normalises hyper-arousal in CaMKII autophosphorylation deficient mice. a r t i c l e i n f o Article history: Received 21 May 2013 Accepted 22 May 2013 Available online 31 May 2013 Keywords: AlphaCaMKII Autophosphorylation Alcohol Conditioned place preference Reinforcement Locomotion a b s t r a c t The autophosphorylation of alpha Ca 2+ /calmodulin dependent protein kinase II (CaMKII) is important for memory formation and is becoming increasingly implicated in the development of drug addiction. Previous work suggests that CaMKII acts via the monoaminergic systems to facilitate the establishment of alcohol drinking behaviour. The present study aims to investigate whether CaMKII autophosphoryla- tion deficient CaMKII T286A mice show a difference in the rewarding properties of alcohol (2 g/kg, i.p.), as measured by conditioned place preference (CPP). We found that alcohol-induced CPP could be established at an accelerated rate in CaMKII T286A compared to wild type (WT) mice. Hyperactivity/hyper-arousal induced by the test environment was normalised by alcohol in the CaMKII T286A , but not WT mice. This effect could be conditioned to the test environment and may suggest enhanced negative reinforcing action of alcohol in CaMKII autophosphorylation deficient mice. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Calcium/calmodulin dependent protein kinase II (CaMKII) is a major post-synaptic density protein. It plays a key role in synaptic plasticity in the glutamatergic system and is known to be important for learning and memory formation [1,2]. Alpha-CaMKII (CaMKII) is part of the calcium (Ca 2+ ) signalling cascade in cells and is typ- ically inactive under basal cellular conditions. Upon Ca 2+ influx CaMKII is able to phosphorylate neighbouring subunits in the holoenzyme at the threonine 286 residue. This autophosphory- lation mechanism prevents CaMKII from reverting to its resting ∗ Corresponding author at: Section of Addiction Medicine, Department of Psychi- atry and Psychotherapy, Friedrich-Alexander-University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. Tel.: +49 9131 85 36896; fax: +49 9131 85 36002. E-mail address: Christian.Mueller@uk-erlangen.de (C.P. Müller). state even after Ca 2+ levels drop to baseline levels. It is this switch to a Ca 2+ independent state which allows signals to be potentiated for longer within the cell, leaving a lasting imprint along the pathway, and thereby accelerating learning [3]. Modifications in CaMKII expression in the brain have pre- viously been linked to drugs of abuse [4–6]. Alcohol treatment has also been shown to induce increases in CaMKII in prena- tal and postnatal rat cerebral cortex [7], an effect which can be attributed to Ca 2+ influx during chronic alcohol exposure. How- ever, chronic ethanol treatment has also been shown to have no effect on CaMKII expression levels in human embryonic kidney (HEK) 293 cells [8]. Recent evidence implicates CaMKII in the establishment of drinking behaviour. CaMKII autophosphoryla- tion deficient mice consume alcohol significantly less than their wild-type litter mates, especially at higher percentage alcohol solutions [9]. In vivo microdialysis showed that an acute alco- hol challenge induces a dopamine (DA) increase in the nucleus accumbens (NAcc) of wild-type mice, a response which is entirely 0166-4328/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbr.2013.05.045