One limitation of this study is that [123I]5-IA measures the availability of the β2-subunit of the nAChR, primarily the α4β2-subunit, but other subunits also contribute to the regulation of the nAChR by tobacco smoking. Notably, the β2-subunit has been linked primarily to the reinforcing effects of nicotine22, 83, 84 and combines with the α3-6 subunits. Importantly, different β2*-subunit combinations appear to be differentially regulated by nicotine, with α3/α6 and α6α4β2* and α5α4β2* not upregulating or decreasing in response to nicotine38, 85-88 while α6β2 (nonα4) nAChR increase in response to nicotine88. Notably, nAChR subunit expression varies regionally, and differential regulation of these distinct subunit combinations that are measured by a single nicotinic agonist ligand such as [123I]5-IA will result in regional differences in the degree of upregulation in smokers and the degree of receptor normalization during abstinence. Thus, we are likely measuring the β2-subunit in combination with α3-6 subunits leaving the in vivo measurement of the β3-subunit and α7-subunit for the future, with further radiotracer development. Both the α7- and β3-subunit have been implicated in modulating dopamine release14, 89 and thus,
