Since the stem cell-derived neuronal cultures are likely to be most similar to neurons present in early stages of human development, and not those in adults responding to repeated nicotine stimulation such as in addiction, we do not suggest that the altered activity found in N398 explains addiction behaviors. Instead, we believe that our results predict that naïve neurons in human brains of individuals with the N398 variant would exhibit enhanced response from initial nicotine exposure, perhaps contributing to development of addiction, followed by a lack of response, leading to an unsatisfied craving for additional stimulus. However, the use of iPSC-derived neuron cultures may be used to screen cessation therapies for smokers carrying specific genetic variants. Methods for genetic screening of smoking-related variants are already possible5152 and tailoring cessation therapy to selected variants is effective53. Adding stem cell-based drug screening to this process is likely to produce even greater success. This stem cell-based approach serves as a proof-of-principle to study how addiction risk-associated gene variants may affect human neuronal functions. Continuing these studies is likely to lead to a better understanding of the impact of gene variants on human behavior and may identify strategies for intervention in addiction.
