Research ArticleAddiction

Molecular Mechanism for a Gateway Drug: Epigenetic Changes Initiated by Nicotine Prime Gene Expression by Cocaine

Science Translational Medicine  02 Nov 2011:
Vol. 3, Issue 107, pp. 107ra109
DOI: 10.1126/scitranslmed.3003062

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Another Reason to Shun Cigarettes

Illicit drugs sap the strength of the human population. Yet, our efforts to control their use, through law enforcement or medicine, are weak and largely ineffectual. Most drugs of abuse act on the reward centers of the brain, setting up positive incentive cycles that lead to addiction. These mechanistic insights have not yet yielded treatments that curtail drug use, but new research has delivered some potentially practical knowledge. Levine et al. now show that nicotine alters the brain to make it more susceptible to cocaine’s addicting effects, and suggest that interfering with this reprogramming may rein in cocaine abuse.

The authors pretreated mice with nicotine to mimic the effects of smoking and detected an increase in the behavioral and neuronal activity responses that mice typically exhibit when given cocaine, relative to animals that had not been pretreated. In contrast, cocaine did not have the reciprocal effect on nicotine responses. So, how does nicotine engineer this cocaine supersensitivity? By taking a close look at histone proteins—which package DNA as chromatin—in the reward centers of the brain (the striatum), the authors found that certain histones were hyperacetylated, a state that results in augmented gene expression, consistent with the exaggerated response to cocaine. Encouraging, but preliminary at this point, is the idea that activators of histone deacetylases, which decrease histone acetylation, might counteract the effect of nicotine and perhaps other stimuli that prime the response to cocaine. Confining the action of these putative drugs to the striatum would enhance their chances of achieving selective efficacy and low toxicity, although the tools for targeting these agents are not yet available.

An epidemiological analysis described in the paper by Levine et al. reinforces the urgency of translating these results: Most cocaine addicts began using the drug after they started smoking cigarettes, as would be expected if the mechanism operative in mice is mimicked in humans. Cocaine abusers are often administered nicotine replacement therapy to help curb their smoking habits; if the authors’ findings hold up in humans, nicotine replacement therapy might actually exacerbate the patient’s cocaine addiction, a highly undesirable side effect. Finally, using cocaine while smoking increases the risk of becoming dependent on the drug: another healthy reason not to smoke.


  • Present address: Department of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, I A-1090 Vienna, Austria.

  • These authors contributed equally to this work.