Tobacco smoking is the leading preventable cause of morbidity and mortality in the world, yet despite decades of public awareness campaigns on the adverse health consequences of smoking, 21.5% of adults in the U.S. are daily smokers. The reinforcing effects of nicotine are mediated in part via its effects on α4β2 nicotinic acetylcholine receptors, which result in activation of dopamine (DA) cells and increased release of DA in the nucleus accumbens (NAc). In fact, the ability of most addictive drugs to increase DA in the NAc is believed to be a common mechanism through which drugs of abuse exert their reinforcing effects. However, preclinical studies have shown that nicotine also results in release of endogenous opioids, which is also likely to contribute to its reinforcing effects because nicotine is not reinforcing in mice that do not express mu-opioid receptors. Thus, a more complete understanding of the acute and chronic effects of nicotine on the endogenous opioid system in humans might provide improved strategies for medication development for the treatment of nicotine dependence. In this study, we propose to investigate whether nicotine at the dose delivered through a cigarette (1-2 mg) will increase the release of endogenous opioids. We will also determine whether smokers have adaptations in the opioid system compared with nonsmokers. We will test 20 smokers and 20 nonsmokers. Outcome measures include: 1) displacement of 11Ccarfentanil binding, secondary to the release of endorphins by nicotine;2) upregulation of 11Ccarfentanil specific binding in smokers compared with nonsmokers;3) 11Ccarfentanil specific binding as a function of the mu-opioid receptor A118G polymorphism;and 4) correlation between self-report measures of nicotine effect and 11Ccarfentanil binding profile. During the past year, we have initiated the study and completed testing of 6 subjects. Because study enrollment is ongoing, we have no findings to report at this time.

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National Institute on Drug Abuse
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