Given conflicting data associating the serotonin system with the regulation of emotion as well as the well-documented association between negative affect and smoking (Copeland, Kulesza, & Hecht, 2009; Leventhal, Waters, Kahler, Ray, & Sussman, 2009), it may be that the gene exerts an effect on smoking behavior in complex ways that are not completely understood but which at some level effect neurobiological pathways shared by both nicotine and serotonin. Differences in behavioral phenotypes associated with smoking may be partly related to the effects of the gene on serotonin transport (and availability) which in turn, affect the activation/suppression of very fundamental neurobiological mechanisms related to processing of emotional information. These emotional processing systems and structures are likely to be very primitive in the sense that they are phylogenetically very old and are activated by motivationally relevant stimuli that predispose the organism toward appetitive (approach) or defensive (avoidance) behavior. A paradigm such as affective picture modulation using the acoustic startle response (ASR) may provide a sensitive measure of the functional impact the 5-HTTLPR genotype on brain mechanisms associated with appetitive and defensive systems, particularly in response to events that have clear motivational relevance to the smoker: nicotine administration and deprivation.
