Reduced CYP2B6 metabolism influences smoking initiation and treatment response: i

描述（由申请人提供）：目前约有21%的美国成年人是吸烟者，近年来吸烟率没有下降。吸烟每年在全球造成约300万人死亡，虽然约80%的吸烟者希望戒烟，但大多数人都失败了。由于持续吸烟和长期戒烟率低，吸烟仍然是一个重大的健康问题。该项目旨在更好地了解人们在获得吸烟风险和戒烟成功方面的差异背后的机制，并制定更好的预防策略和治疗方法。家庭和双胞胎研究表明，吸烟的许多方面都有潜在的遗传成分，具有药物代谢酶CYP2B6基因变异的人，导致酶减少（CYP2B6代谢缓慢），更有可能成为尼古丁依赖者，并且在戒烟后，会经历更多的渴望和戒断；他们的戒烟率较低，但对戒烟药物安非他酮和伐尼克兰的反应更好。CYP2B6不太可能参与尼古丁的整体代谢，但它存在于大脑中，可以参与内源性化合物的局部代谢，以及尼古丁及其代谢物（如去甲尼古丁）在大脑中的水平。本研究将探讨大脑CYP2B6减少在CYP2B6缓慢代谢者和正常代谢者吸烟相关行为差异中的作用。将在大鼠中使用一种新的方法来模拟人类CYP2B6缓慢代谢者的大脑CYP2B6代谢减少，其中一种基于特定机制的化学抑制剂将被直接注射到大鼠的脑室中。该程序将与大鼠尼古丁自我给药范例结合使用，以研究脑CYP2B6代谢减少在增加尼古丁依赖率和风险中的作用。抑制大脑CYP2B后，大鼠获得尼古丁自我给药的比率应该更高，因为大脑中的尼古丁水平应该比不受抑制时更高，从而增加尼古丁的强化。该脑CYP2B6抑制程序还将与尼古丁戒断大鼠模型结合使用，以研究脑CYP2B6代谢减少在戒烟严重程度以及对安非他酮和伐尼克兰的反应中的作用。由于大脑CYP2B抑制，大鼠在尼古丁治疗停止后应该会经历更多的戒断症状，因为在接受尼古丁治疗时，大脑暴露于尼古丁增加，去甲尼古丁水平降低。同样，这些大鼠服用安非他酮和伐尼克兰后，戒断症状会得到更大的减轻。该项目的结果可能会导致进一步研究大脑CYPs在药物滥用和成瘾中的作用，并为开发更好的戒烟治疗策略提供新方法。脑cypp介导的酶代谢领域是非常独特的；检查操作大脑cypp介导的代谢是新颖的，代表了一个令人兴奋的新的研究途径。

DESCRIPTION (provided by applicant): About 21% of US adults are current smokers and smoking rates have not declined in recent years. Smoking causes about 3 million deaths a year world-wide, and while roughly 80% of smokers desire to quit smoking, most fail. Because of continued smoking acquisition and low long term abstinence rates, smoking remains a significant health problem. This project aims to gain a better understanding of the mechanisms behind the variation between people in their risk for acquisition of smoking and their success in smoking cessation and to develop better prevention strategies and treatments. Family and twin studies illustrate an underlying genetic component to many aspects of smoking, and people with genetic variants of the drug metabolizing enzyme CYP2B6, that result in reduced enzyme (slow CYP2B6 metabolizers), are at greater risk for becoming nicotine-dependent, and upon stopping smoking, experience more craving and withdrawal; they have lower quit rates but respond better to the cessation drugs bupropion and varenicline. CYP2B6 is unlikely to contribute to overall nicotine metabolism, but is present in the brain where it can contribute to local metabolism of endogenous compounds, and to the brain levels of nicotine and its metabolites, such as nornicotine. This proposal will investigate the role of reduced brain CYP2B6 in the differences in smoking- related behaviors between CYP2B6 slow and normal metabolizers. A novel procedure will be used in rats to model reduced brain CYP2B6 metabolism in human CYP2B6 slow metabolizers, wherein a specific mechanism-based chemical inhibitor will be injected directly into rat brain cerebral ventricles. This procedure will be used in combination with a rat nicotine self-administration paradigm to investigate the role of reduced brain CYP2B6 metabolism in the increased rate and risk of becoming nicotine dependent. The rate of acquisition of nicotine self-administration by rats should be higher with inhibition of brain CYP2B, as there should be higher nicotine levels in the brain than without inhibition, increasing nicotine's reinforcement. This brain CYP inhibition procedure will also be used in combination with a rat model of nicotine withdrawal to investigate the role of reduced brain CYP2B6 metabolism in severity of withdrawal from smoking, and in the response to bupropion and varenicline. With brain CYP2B inhibition, the rats should experience increased withdrawal symptoms upon cessation of nicotine treatment, due to increased brain exposure to nicotine and reduced nornicotine levels while receiving nicotine. Similarly, these rats should experience greater attenuation of withdrawal symptoms with bupropion and varenicline. The results of this project may lead to further investigation of the role of brain CYPs in drug abuse and addiction, and to novel approaches for development of better treatment strategies for smoking cessation. The field of brain CYP-mediated enzyme metabolism is highly unique; examining manipulation of brain CYP-mediated metabolism is novel and represents an exciting new avenue of research. PUBLIC HEALTH RELEVANCE: About 21% of US adults are smokers and smoking causes about 3 million deaths a year world-wide. Smoking rates have not declined in recent years in the US indicating many people are still becoming smokers and only some are able to stop smoking. This project takes a novel approach to understanding the mechanisms whereby some people are more vulnerable to both becoming and remaining smokers, and whereby some smokers respond better to cessation drugs than others. Ultimately these studies may be useful in developing better smoking prevention strategies and treatments.