Sequence of Interaction of Factors Leading to Smoking Addiction.Social, cultural and individual risk factors increase the probability of smoking initiation. The nicotine from tobacco smoke enters the brain and binds to nicotinic cholinergic receptors, which modulates the neurotransmitter release that produces the behavioral effects of positive reward and stress reduction.Some nicotinic receptors rapidly desensitize and this plus changes in other neurotransmitter systems results in tolerance which stimulates repeated smoking both to maintain positive reward and to avoid withdrawal symptoms. Each cycle of smoking increases behavioral conditioning to environmental cues, which increase craving, which in turn helps strengthen and maintain the smoking cycle leading to addiction. Individual risk factors such as genetics, age, sex, stress, psychiatric disorder and substance abuse can interact with metabolism and neurobiologic and behavioral effects to alter the risk of developing smoking addiction.(Constructed and elaborated from data in Benowitz, N.L. et al. NEJM, 362: 2295 – 2303, 2010) ©2012 NBEP