The nAChRs are pentameric ligand-gated cation channels consisting of some combination of nine α (α2–α10) and three β (β2–β4) subunits. Mouse knockout models have demonstrated that the α4 and β2 subunits, the most widely expressed forms in the brain, are critical for nicotine self-administration and nicotine-induced dopamine release in the VTA (31, 32). Mouse knockout models for α5, α3 and β4 subunits have also been created, although only in heterozygous form for α3 as the complete knockouts suffer severe physical abnormalities and die within weeks of birth (33). Their responses to nicotine have not been extensively analyzed yet, though in general these animals have reduced sensitivity to nicotine-induced seizures and the locomotor suppressant effects of nicotine (reviewed in (34), Supplementary Table 1). Animal models will also be useful in determining whether these nAChR subunits have a direct role in mediating lung cancer or COPD independently of smoking behaviors.
