ALCO_CAMK

Alpha CaMKII autophosphorylation as a mechanism to regulate alcohol consumption

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 Obiettivo del progetto (Objective)

'Understanding molecular basis of alcohol addiction still remains a great challenge for science and at the same time the only chance for designing successful molecular therapy. Calcium and calmoduline-dependent kinase II alpha (alpha CaMKII) is a major protein of forebrain glutamatergic neurons with well established function in various aspects of cell physiology, e.g. actin remodelling. Alcohol-induced actin remodelling has been recently implicated in control of alcohol resistance and consumption in mice. Interestingly, we have found that mice with mutated autophosphorylation domain (T286A) of alpha CaMKII (Giese et al., 1998) have decreased basal level of polymerized actin as well as alcohol consumption and preference (Radwanska, unpublished observations). Thus we would like to hypothesis that alpha CaMKII autophosphorylation is a key modulator of alcohol-induced actin-remodelling and thus alcohol consumption and preference. To verify our hypothesis we shell accomplish the following objectives: - to test whether autophosphorylation of alphaCaMKII regulates acute behavioural response to alcohol as well as to long-term alcohol drinking; - to identify brain regions in which autophosphorylation of alphaCaMKII contributes to actin remodelling; - to investigate which signalling pathways connect CaMKII autophosphorylation in mutant mice with actin remodelling; - to test whether autophosphorylation of alphaCaMKII regulates actin remodelling induced by alcohol; Here we will establish the role of CaMKII autophosphorylation in actin remodelling and alcohol preference. Toward this end, integrative approach will be used: behavioural studies with mutant mice (CaMKIIT286A) will be combined with various molecular and biochemical analyses of protein expression and phosphorylation. This research will advance our understanding of molecular basis of alcohol preference and alcohol consumption, which are the critical prerequisites for alcohol addiction.'

Introduzione (Teaser)

Researchers have gathered data on what happens in your brain the morning after drinking all night. The outcome might depend on your genes.

Descrizione progetto (Article)

Millions of people suffer from alcoholism worldwide. Alcoholism not only affects the addicted and their families, but also has socioeconomic consequences, such as financially burdening health care and welfare systems. Thus, it is important to further our biological understanding of alcohol addiction in order to develop more effective treatment and prevention.

The project 'Alpha CaMKII autophosphorylation as a mechanism to regulate alcohol consumption' (ALCO_CAMK) worked on two important ways to further our knowledge of the disease and future possibilities for treatment. First, the project focused on forming an animal model of alcohol addiction-related behaviours. To do this, a longitudinal study was performed.

Detailed analysis of mouse behavior in social groups and behavioural traits, previously shown in humans as precursors to alcoholism (impulsivity, anxiety etc.), were studied. The mice were then studied with unlimited access to alcohol for 70 days. Analysing for correlations between the behavioural traits and addiction-like behavior, the data suggested one between high levels of anxiety-related traits and high impulsivity.

The second part of the project was focused on the connection between the autophosphorylation of calcium and CaMKII and the development of alcohol addiction-related behaviours. CaMKII-T286A mutant mice were compared to their wild-type littermates and it was discovered that the CaMKII autophosphorylation-deficient mutants had different behavioural responses to alcohol. For example, the mutants had a decreased psychostimulant response to the alcohol injection.

Tests also showed a clear split of high and low motivation for alcohol among the wild mice after chronic alcohol treatment. Yet, the mutant mice mainly remained in the middle of this scale.

The ALCO_CAMK project established a new animal model for alcohol addiction and found that the autophosphorylation of CaMKII is important for the regulation of alcohol addiction-related behaviours. The discovery of the effects of CaMKII on behavioural effects of alcoholism will hopefully spur the creation of successful new molecular strategies for treating alcoholism.