nAChR channels are pentameric and comprised of various types of subunits. Twelve α subunits and three β subunits have been cloned, and various isoforms containing both α4 and β2 subunits are the most abundant in mammalian brain.13 nAChRs have a large dynamic range with respect to agonist activation, but this is partially explained by the presence of heteromers with different stoichiometric composition of subunits with different sensitivities. Measurements indicate that (α4)3(β2)2 is a low-sensitivity subtype (LS), whereas (α4)2(β2)3 is of high sensitivity (HS).14 Chronic nicotine exposure upregulates nAChRs in a complex process involving molecular chaperoning,15, 16 and upregulation of α4β2 receptors by nicotine favors the HS form.17 Lowered sensitivity to psychoactive drugs is generally believed to correlate with increased risk of substance dependence, and it has been suggested that increased expression of LS relative to HS nAChRs in the central nervous system would increase risk of ND.18
