Drug addiction is a complex psychiatric disorder. Several predisposing factors can contribute to the vulnerability to develop this pathology, including environmental and genetic ones. Although smoking prevalence has declined in recent years, certain subpopulations continue to smoke at high rates. Human genetic studies have reported a strong association between a non-synonymous single nucleotide polymorphism (SNP) in the nicotinic acetylcholine receptor (nAChR) α5 subunit gene (rs16969968), and the risk for heavy smoking. The rs16969968, as well as other SNPs in the α5 gene, were further associated with abuse of other substances, including cocaine and alcohol. We aim at better understanding how α5 containing nAChRs influence addiction-like processes, as well as the brain circuits implicated, using a combination of approaches including transgenic rats and drug self-administration procedures. Our data suggest that alterations in α5 containing nAChRs represent a key factor underlying vulnerability to abuse of multiple substances. These receptors may be promising novel therapeutic target, in particular for preventing relapse after abstinence. This work further opens up for refined genetic analysis in human cohorts, based on specific addiction-related phenotypes.