Impact of nicotine metabolism on brain dopamine transmission

尼古丁代谢对大脑多巴胺传递的影响

• 批准号: 8873323
• 负责人: Bernard Le Foll
• 金额: $ 14.75万
• 依托单位: CENTRE FOR ADDICTION AND MENTAL HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8873323
• 关键词: Abstinence; Accounting; Area; Behavior; Behavioral; Binding; Brain; Breathing; Cigarette; Clinical Research; Consumption; Cotinine; Data; Dopamine; Dopamine Receptor; Drug Addiction; Drug usage; Eating; Enzymes; Excision; Exhibits; Genetic; Genotype; Human; Image; Impact evaluation; Individual; Laboratories; Measures; Mediating; Mental Health; Metabolic; Metabolic Clearance Rate; Metabolism; Methods; Negative Reinforcements; Neurotransmitters; Nicotine; Nicotine Dependence; Participant; Pathway interactions; Perception; Phenotype; Positive Reinforcements; Positron-Emission Tomography; Property; Public Health; Raclopride; Recruitment Activity; Rewards; Scanning; Smoke; Smoker; Smoking; Smoking Behavior; System; Tobacco; Tobacco Dependence; Tobacco smoking; Variant; Visit; Withdrawal; addiction; craving; cytochrome P-450 CYP2A6 (human); dopamine system; drug of abuse; incentive salience; pleasure; preclinical study; public health relevance; radiotracer; response; smoking cessation; transmission process

 DESCRIPTION (provided by applicant): Tobacco dependence is a serious public health problem. An understanding of why cigarette use is so hard to quit may come from an understanding of the mechanisms of action of nicotine. Nicotine is the primary psychoactive substance in cigarettes, believed to mediate their addictive properties through the rate of clearance of nicotine from the body. Fast metabolizers smoke more and find it harder to stop smoking than slow metabolizers. Despite the characterization of the behavioral differences between fast metabolizers and slow metabolizers, differences between the two in brain systems that underlie smoking have not been delineated. Dopamine is the final common path of all addictive substances and activation of the dopamine system is thought to underlie the addictive potential of nicotine. In our laboratories, we use Positron Emission Tomography (PET) imaging to measure dopamine transmission in the human brain. At the Centre for Addiction and Mental Health, we have developed a method to study the impact of tobacco smoking on dopamine transmission in the human brain. With the use of the radiotracer [11C]-(+)-PHNO, we have the most sensitive method in the world to study changes in dopamine levels in response to smoking. The purpose of the present proposal will be to provide the first direct evaluation of the impact of different rates of nicotine metabolism on dopamine transmission. To this end, we will image the dopamine system either at baseline or after smoking. Comparisons will be made between fast metabolizers and slow metabolizers. It is hypothesized that, in keeping with our preliminary data, slow metabolizers will exhibit greater increases in dopamine levels following smoking. Non-treatment seeking participants will visit our PET centre for two PET scans that will be separated by one week. During one scan, the participant will be abstinent from smoking and just prior to the other, the participants will smoke a cigarette. Participants will then underg PET scans. Subjective measures of pleasure and craving will also be taken, as will smoking topography, to assess the effect of rate of metabolism of perception of cigarettes.

 描述（由申请人提供）：烟草依赖是一个严重的公共卫生问题。要了解为什么吸烟如此难以戒掉，可能需要了解尼古丁的作用机制。尼古丁是香烟中主要的精神活性物质，据信通过尼古丁从体内的清除率来调节其成瘾特性。代谢快的人比代谢慢的人吸烟更多，而且戒烟更困难。尽管描述了快速代谢者和慢速代谢者之间的行为差​​异，但吸烟背后的两者大脑系统之间的差异尚未被描绘出来。 多巴胺是所有成瘾物质的最终共同途径，多巴胺系统的激活被认为是尼古丁成瘾潜力的基础。在我们的实验室中，我们使用正电子发射断层扫描 (PET) 成像来测量人脑中的多巴胺传输。在成瘾和心理健康中心，我们开发了一种方法来研究吸烟对人脑中多巴胺传输的影响。通过使用放射性示踪剂 [11C]-(+)-PHNO，我们拥有世界上最灵敏的方法来研究吸烟引起的多巴胺水平的变化。 本提案的目的是对 不同尼古丁代谢率对多巴胺传递的影响。为此，我们将在基线时或吸烟后对多巴胺系统进行成像。将在快代谢者和慢代谢者之间进行比较。据推测，根据我们的初步数据，慢代谢者在吸烟后多巴胺水平会出现更大的增加。 非寻求治疗的参与者将前往我们的 PET 中心进行两次 PET 扫描，两次扫描相隔一周。在一次扫描期间，参与者将戒烟，而在另一次扫描之前，参与者将吸烟。然后参与者将接受 PET 扫描。还将采取愉悦和渴望的主观测量，以及吸烟地形，以评估香烟感知的新陈代谢率的影响。