This interaction promotes a variety of neurophysiological changes including chaperone-mediated nAChR upregulation [30,35,37,51,52,53,54], activation of the mesocorticolimbic reward and reinforcement pathways [55,56], enhanced synaptic plasticity [57,58,59,60], and enhanced neuronal firing [53,60,61,62,63], ultimately leading to the development of nicotine addiction [33,64] (Table 1). This evidence concerns the gene CHRNA4 and nicotine dependence.