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Novel insights into nicotine dependence: The hope for new cessation therapeutics

Creative Commons 'BY-ND' version 4.0 license

Tobacco smoking is considered to be one of the leading causes of preventable death worldwide, and nicotine is the primary reinforcer of tobacco dependence. Current therapeutics for tobacco cessation focus on alleviating the rewarding effects nicotine, but they are only modestly efficacious. Therefore, alternative therapeutics with greater efficacy is required. In this dissertation, the mechanism of nicotine dependence was investigated with different approaches to provide a foundation for the development of novel nicotine cessation treatments. As nicotine metabolism is involved in regulating the reinforcing effects of nicotine, we have demonstrated that inhibiting CYP2A6, the major enzyme responsible for metabolizing nicotine, decreases nicotine self-administration in mice. To address the dramatic increased use of e-cigarettes, we have established a vapor self-administration model in rodents to allow us study how nicotine vapor impact brain circuitry. As the aversive symptoms during nicotine withdrawal are also major factors that prevent people from quitting smoking, the exact neurobiological mechanisms of nicotine withdrawal remain to be elucidated. While previous studies have emphasized cholinergic signaling in the medial habenula in nicotine withdrawal (Gorlich et al., 2013; Dao et al., 2014; Shih et al., 2014), we have shown that purinergic signaling plays an important role in controlling medial habenula neuronal activity. Together, our studies provide insight into the biological mechanisms underlying nicotine dependence and a foundation to further advance novel nicotine cessation treatments.

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