Mice lacking the α4 subunit generated by Marubio et al. (1999) no longer express high-affinity binding sites. α4 KO mice also show a reduced antinociceptive effect of nicotine on the hot-plate test and diminished sensitivity to nicotine in the tail-flick test. Tapper and colleagues generated knock-in mice that express the Leu9′Ser mutation, expressing a receptor hypersensitive to nicotine. They found that selective activation of these receptors with low doses of nicotine replicates tolerance and sensitization stimulated by chronic nicotine administration, suggesting a role for this subunit in various smoking behavior phenotypes (Tapper et al. 2004). This mutant mouse model was also used by Labarca et al. (2001) and others who found that the hypersensitive mice display increased anxiety and poor motor learning, which is eliminated by low levels of nicotine administered i.p. Quantification of nAChR subunit gene expression indicates that posterior ventral tegmental area (pVTA) neurons express higher levels of α4 (as well as α6 and β3) transcripts than anterior VTA neurons (Zhao-Shea et al. 2011). Infusion of α-conotoxin MII into the VTA blocked activation of pVTA dopaminergic neurons in
