Clinically significant sex differences have been observed in nicotine addiction. Women smokers have greater risk for negative health consequences (e.g., lung cancer), even at lower volumes of smoking than men. Moreover, rates of smoking among women are not diminishing as quickly as men. This may in part be accounted for by lower efficacy of standard pharmacological smoking cessation aids (e.g., nicotine replacement therapy) in women, compared with men. As such, novel pharmacological smoking cessation aids, with efficacy in women, would be of high clinical value. A single nucleotide polymorphism in the COMT gene (i.e., Val158Met) has been shown to have functional, often sexually-dimorphic effects on cognitive and behavioral phenotypes associated with addiction vulnerability. Individuals with the Met allele substitution have diminished functionality of the COMT enzyme, which breaks down dopamine, predominantly in the prefrontal cortex but also in ventral striatal regions. As such, Met allele carriers have higher tonic dopamine levels in the prefrontal cortex, while also experiencing reduced nicotine-induced dopamine release in the ventral striatum. These properties are thought to contribute to the Met allele's protective effects in contrast to the Val allele's characterization as the `risk' allele for nicotine dependence. Our recent findings have shown sex-sensitive effects of COMT genotype on withdrawal severity during nicotine abstinence. Specifically, women smokers with the Val/Val genotype reported greater withdrawal severity and more smoking urges, and displayed poorer sustained attention performance after overnight abstinence, compared with female Met carriers. In contrast, withdrawal, smoking urges or cognition measures did not differ by Val158Met genotype in overnight-abstinent men. Given the role of abstinence-related withdrawal, smoking urges and cognitive decrements in risk for smoking relapse, these findings offer a mechanism by which women Met carriers (i.e. with lower COMT enzyme activity) may be `protected', perhaps explaining their higher rates of successful smoking cessation outcomes. The medication tolcapone is a specific COMT inhibitor, which decreases COMT enzyme activity in a manner similar to the effects of the `protective' Met allele. The proposed proof-of-concept study aims to test whether the COMT inhibitor, tolcapone, relative to placebo (a) diminishes symptoms of nicotine withdrawal, smoking urges and cognitive decrements in women smokers during short-term (72-hr) abstinence; and (b) reduces smoking in a laboratory choice paradigm in women smokers following short-term (72-hr) abstinence.

Public Health Relevance

Tobacco-related illnesses are a substantial women's public health concern, accounting for more preventable deaths than all other addictive behaviors combined. Converging evidence supports biological mechanisms contributing to the lower rates of successful smoking cessation in women, relative to men. A pharmacological intervention that could successfully diminish symptoms of nicotine withdrawal or smoking urges in women smokers during short term abstinence would be of high clinical value as it may improve rates of smoking cessation in this population.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Walton, Kevin
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Yale University
Schools of Medicine
New Haven
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DeVito, Elise E; Carroll, Kathleen M; Sofuoglu, Mehmet (2016) Toward Refinement of Our Understanding of the Fundamental Nature of Addiction. Biol Psychiatry 80:172-3