SENSIBALCO

Drug addiction is a chronic relapsing disease that represents a serious health, social and economical burden for which discovery of new effective therapies is a pressing necessity. Among the different theories that have been proposed to explain addiction, the incentive sensitization theory states that repeated exposure to drugs of abuse causes hypersensitivity to drugs and drug-associated stimuli of the neural circuits mediating incentive salience, an important way in which motivational stimuli influence behavior. Drug induced sensitization may play a crucial role both in the initial step in the addiction process and may further explain the increase in drug "wanting," being responsible for the dramatically exaggerated motivation for drugs displayed by addicts and the risk of relapse. Nowadays, there is clear evidence that drug-induced sensitization may be involved in addiction. Recent studies performed in our laboratories have demonstrated that some animals are prone to alcohol-induced behavioural sensitization whereas others are resistant. In this project, we will investigate and characterize the cellular and molecular mechanisms underlying alcohol sensitization and its impact in terms of vulnerability to alcohol addiction in animal models. The main questions that we want to address are 1) what are the cellular and molecular mechanisms underlying alcohol sensitization?; 2) is the anxiety-like behaviour involved in the vulnerability to alcohol sensitization?; and 3) does alcohol sensitization play a role in the transition to alcohol addiction and susceptibility to relapse? In order to answer these questions, we have set-up a consortium between three laboratories with complementary expertise in 1) the vulnerability to alcohol-induced behavioural sensitization and its role in the transition to alcohol addiction (team 1, Inserm Eri 24, University of Amiens), 2) proteomic analysis of brain structures (team 2, Inserm U982, University of Rouen); and 3) neurobiological basis of behavioural sensitization induced by alcohol (team 3, Inserm U952, CNRS UMR7224, UPMC). These scientific skills will allow us to uncover the neurobiological mechanisms involved in alcohol sensitization and its implication in alcohol addiction transition. Our main working hypothesis is that alcohol sensitization produces long-lasting changes in the brain that result in vulnerability to the transition to alcohol addiction and the high risk of relapse. In tasks 1, 2, 3 and 4, team 1 directed by M Naassila will explore the cellular/molecular and behavioural mechanisms involved in alcohol sensitization and demonstrate if alcohol sensitization is involved in the transition to alcohol addiction and the susceptibility to relapse in a unique and pertinent model of alcohol addiction. In task 1, team 2 directed by D Vaudry will identify the proteins that are differentially expressed between sensitized versus resistant animals, using a proteomic approach. Once targets will be identified, pharmacological tools (or gene knockdown) will be used to reduce and or prevent sensitization. Finally, in task 5, team 3 directed by JP Tassin, will test the potential neurobiological mechanism underlying the vulnerability to alcohol sensitization, i.e. the NA/5-HT uncoupling mechanism. We will use state-of-the-art preclinical models of addiction developed in Amiens and combine them with several techniques to study the role of alcohol sensitization in alcohol addiction. In addition, we dispose of a wide array of cellular/molecular, electrophysiology techniques that will allow us investigating neurobiological mechanism that may underlie alcohol-induced sensitization. In conclusion, this research project constitutes a unique, multi-level approach that should provide a clear picture of the mechanisms involved in alcohol sensitization and its role in alcohol addiction. Thus it will provide original data for this serious health, social and economical problem.