Modeling human polymorphisms for nicotine addiction in mice
Nicotine addiction presents a serious social and public health problem. Worldwide, 100 million people are expected to die this century from the consequences of nicotine addiction. Human genetic studies have revealed recently that human coding and non-coding polymorphisms (at locus 15q25) for alpha3*, alpha5* and beta4* nicotinic acetylcholine receptors (nAChRs) are correlated with smoking and/or lung cancer. Strikingly, neither alpha3*, alpha5* nor beta4*-nAChRs have been studied experimentally using animal models of nicotine?s neuronal, reinforcing or cognitive effects. We will focus on the subunits containing these polymorphisms, as revealed recently by three independent consortia, and directly implicated in nicotine addiction by one of them. The aim of this project is to carry out a multi-level analysis using genetic, neuronal and behavioral mouse models to determine the respective roles of alpha3*, alpha5* and beta4*-nAChR subtypes for which human polymorphisms point to a role in nicotine addiction. We will be using tools that have been proven to be efficient for our previous study of alpha4beta2*nAChRs Finally, significant results would stimulate the interest of pharmaceutical companies in developing therapeutic nicotinic compounds based on this entirely new, undeveloped pharmacology.
cellular and genetic approaches, Imaging techniques, Molecular, Animal models, Behavioural, Electrophysiology, Pharmacology, Substance use disorders
2011 - 2014
Uwe Maskos (Coordinator)