Molecular Mechanisms Underlying Behaviors Related to Nicotine Addiction

Tobacco smoking results in more than 5 million deaths each year and accounts for almost 90% of all deaths from lung cancer. Nicotine, the major reinforcing component of tobacco smoke, acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are allosterically regulated, ligand-gated ion channels consisting of five membrane-spanning subunits. Twelve mammalian alpha subunits (alpha 2-alpha 10) and beta subunits (beta 2-beta 4) have been cloned. The predominant nAChR subtypes in mammalian brain are those containing alpha 4 and beta 2 subunits (denoted as alpha 4 beta 2* nAChRs). The alpha 4 beta 2* nAChRs mediate many behaviors related to nicotine addiction and are the primary targets for currently approved smoking cessation agents. Considering the large number of nAChR subunits in the brain, it is likely that nAChRs containing subunits in addition to alpha 4 and beta 2 also play a role in tobacco smoking. Indeed, genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the alpha 5, alpha 3, and beta 4 nAChR subunits, respectively, has been shown to increase vulnerability to tobacco dependence and smoking-associated diseases including lung cancer. Moreover, mice in which expression of alpha 5 or beta 4 subunits has been genetically modified have profoundly altered patterns of nicotine consumption. In addition to the reinforcing properties of nicotine, the effects of nicotine on appetite, attention, and mood are also thought to contribute to establishment and maintenance of the tobacco smoking habit. Here we review recent insights into the behavioral actions of nicotine and the nAChRs subtypes involved, which likely contribute to the development of tobacco dependence in smokers.