Author response: Translational control of nicotine-evoked synaptic potentiation in mice and neuronal responses in human smokers by eIF2α

Nicotine addiction is a serious public health problem. People who start using nicotine during adolescence are more likely to become addicted to it during adulthood, but the reasons for this are not well understood. Nicotine causes long-lasting changes in the brain that are responsible for the feelings of pleasure and reward. In particular, nicotine strengthens the connections between neurons at structures called synapses and increases communication between reward-related neurons in key reward areas of the brain. This hijacking of the natural reward system requires new proteins to be made. However, the relationship between protein synthesis and adolescents being particularly vulnerable to nicotine addiction was not known. In a related study, Huang et al. found that the reduced activity of a protein called eIF2α, which controls the production of new proteins, accounts for why adolescents are more likely to become addicted to cocaine than adults. Thus, Placzek et al. wanted to know whether the same was true for nicotine and whether the proteins controlled by eIF2α are involved in the way human nicotine addicts experience reward. Placzek et al. found that adolescent mice are more susceptible than adult mice to the changes in synaptic strength that are caused by nicotine. This increased susceptibility results from reduced activity levels of the protein eIF2α. Reducing the activity of eIF2α in adult mice made their synapses as likely to change strength in response to nicotine as the synapses of adolescent mice. Placzek et al. also used a technique called functional magnetic resonance imaging and found that compared to non-smokers, the brain activity of human smokers was significantly reduced when given a natural reward. Further studies revealed a variation in the gene encoding the eIF2α protein that affects how smokers respond to a reward, suggesting that this variant is linked to the likelihood that a person will be addicted to nicotine. This work raises several important questions. In addition to regulating the initial adaptive changes induced in the brain by nicotine, does eIF2α activity affect compulsive nicotine use? If so, could targeting parts of the eIF2α pathway help treat nicotine addiction? Finally, further studies could explore whether the gene variant identified by Placzek et al. affects how users of other drugs (such as cocaine or alcohol) respond to natural rewards.

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