Constitutional mechanisms of vulnerability and resilience to nicotine dependence

Abstract

The core nature of nicotine dependence is evident in wide variations in how individuals become and remain smokers. Individuals with pre-existing behavioral traits are more likely to develop nicotine dependence and experience difficulty when attempting to quit. Many molecular factors likely contribute to individual variations in the development of nicotine dependence and behavioral traits in complex manners. However, the identification of such molecules has been hampered by the phenotypic complexity of nicotine dependence and the complex ways molecules affect elements of nicotine dependence. We hypothesize that nicotine dependence is, in part, a result of interactions between nicotine and pre-existing behavioral traits. This perspective suggests that the identification of the molecular bases of such pre-existing behavioral traits will contribute to the development of effective methods for reducing smoking dependence and for helping smokers to quit.

Figure 1

Possible effects of molecular variation on the development of nicotine dependence. The degree of nicotine dependence may be determined by molecular variation in the cascades that are activated directly (green circle) or indirectly (gray and red circles) by nicotine, by molecular variation that indirectly affects nicotine-regulated molecular cascades (triangle), or by variation in molecules that influence the degree of dependence independently of these cascades (star).

Figure 2

Three possible modes of the influence of molecular variation on nicotine dependence. Molecular variation, which involves altered levels or function of a molecule, is caused by genetic variants or non-genetic factors such as developmental anomalies or environmental factors. Molecular variation could increase tendencies toward novelty seeking affiliative attachment, loss of control, cue reactivity, decision-making deficits and automaticity. After exposure, nicotine could serve as a new target for these traits (re-directed target mode). Alternatively, molecular variation could set a basal tone of affect (for example, negative affect, depression, anxiety and stress vulnerability). Nicotine then could provide a ‘therapeutic’ or ‘repair’ function and may potentiate the intensity of negative reinforcement (defect repair mode). Molecular variation also could independently influence behavioral traits and susceptibility or resilience to nicotine dependence (shared, independent influence).