Our results indicate that the N398 variant of CHRNA5 is associated with greater excitability and desensitization in response to nicotine, at least in excitatory cells but also affects the excitability of DA cells. The presence of rs16969968 minor allele in CHRNA5 increases risk of nicotine addiction67. Experiments using heterologous expression of CHRNA5 suggest that the N398 variant alters Ca2+ permeability and mediates nicotine consumption910111440. While these findings reveal potential effects on reward circuitry, as we began this study, we hypothesized that subtle effects of the α5 subunit genetic variants of nAChR would be detectable at the cellular level, especially at the synaptic level.
