A National Research Priority Program of  
the

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Funding Period 2011 - 2013

P11

Functional Validation of Candidate Genes in Nicotine Addiction

Prof. Dr. Rainer Spanagel (Principle Investigator)
Head of Department of Psychopharmacology
Central Institute of Mental Health (ZI) 
University of Heidelberg

J5

68159 Mannheim
+49-(0)621-1703-6251

Fax: +49-(0)621-1703-6255
rainer.spanagel(at)zi-mannheim.de

 

Prof. Dr. Matthias Klugmann (Principal Investigator)

Department of Physiology

The University of New South Wales

Sydney, Australia, NSW 2052

+02-9385-2910

Fax: +02-9385-1485

m.klugmann(at)unsw.edu.au

 

A large body of genetic epidemiological data strongly implicate genetic factors in the aetiology of smoking behaviour related to nicotine dependence in humans. One method to identify genes that may be involved in nicotine dependence is to perform genome-wide association studies (GWAS), in which the genome of individuals in a certain population are analyzed to determine which genes vary from individual to individual. Different variations can be linked to different traits, such as smoking behaviours. And although GWAS offer great promise for detecting candidate genes for the development of chronic smoking behaviour and relapse, and have identified a variety of plausible candidate genes that have been examined for asssociations with smoking behaviour, the evidence linking the contribution of specific genes to smoking behaviour is limited. Animal studies using intravenous self-administration (IVSA) in rodents represent a powerful method to functionally validate candidate genes deriving either from human GWAS approaches or from gene expression profiling studies in animals. IVSA is commonly used as an animal model for studying nicotine addiction in order to elucidate the genetic vulnerability of the development of smoking behaviour in humans, as well as relapse to smoking behaviour following abstinence. Using gene expression profiling via microarray analysis in rodents self-administering nicotine, our laboratory has identified several candidate genes that may be involved in both the acquisition of nicotine self-administration and reinstatement of nicotine-seeking following extinction or abstinence, animal models for the development of nicotine dependence and craving and relapse to smoking behaviour, respectively, in humans. We are currently employing the use of adeno-associated viral (AAV) vectors to functionally validate our candidate genes in IVSA studies. AAV vectors carrying cDNA for, or short hairpin RNA against, specific genes allow the rapid manipulation of gene function in nicotine self-administering animals. Furthermore, we are also employing the use of knockout mice models to further validate our list of candidate genes. In addition, in order to increase the explanatory power of GWAS data associated with nicotine-dependece, we are applying a convergent translational genomics approach to integrate findings from gene expression data in nicotine-dependent rats with GWAS data from the human genetic studies of SPP1226 (P2, 3, 9, 10 ,11) pertaining to either the development of nicotine addiction or relapse behaviour. We are using this information to generate a priority candidate gene list for the entire SPP1226, which we will then validate using nicotine self-administration and relapse in rodents by means of recombinant AAV transfer into brain sites of the reward system.