Effect of nicotine self-administration on endocannabinoids & related lipids

尼古丁自我给药对内源性大麻素的影响

• 批准号: 8061268
• 负责人: Matthew Wallace Buczynski
• 金额: $ 5.13万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8061268
• 关键词: 2-arachidonylglycerol; Address; Affect; Animals; Behavior; Behavior assessment; Behavioral; Biochemical; Biological Assay; Brain; Brain region; Cannabinoids; Cessation of life; Chronic; Development; Disease model; Dose; Endocannabinoids; Ethanolamines; Evaluation; Event; Fatty Acids; Fellowship; Glycerol; Goals; Hydrolase; Individual; Innovative Therapy; Intake; Lead; Ligands; Lipase; Lipids; Mass Spectrum Analysis; Measurement; Mediating; Metabolism; Monoacylglycerol Lipases; Neuraxis; Neurons; Neurotransmitters; Nicotine; Nicotine Withdrawal; Outcome; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Process; Psychological reinforcement; Rattus; Receptor Activation; Relapse; Relative (related person); Rewards; Role; Schedule; Self Administration; Signal Transduction; Synapses; System; Techniques; Tetrahydrocannabinol; Therapeutic; Tissues; Tobacco; Tobacco use; Ventral Tegmental Area; Withdrawal Symptom; activity-based protein profiling; anandamide; cannabinoid receptor; clinically relevant; drug of abuse; enzyme activity; inhibitor/antagonist; interdisciplinary approach; interstitial; neurotransmitter release; new therapeutic target; nicotine abuse; receptor; research study; response; success; vanilloid receptor subtype 1

DESCRIPTION (provided by applicant): The use of tobacco products is one of leading causes of preventable death worldwide. The psychoactive effects of tobacco have been attributed primarily to its content of the bioactive substance nicotine. Current therapies decrease the withdrawal symptoms that occur in addicted individuals upon cessation of nicotine intake. However, this approach has had only moderate success rates in reducing relapse in addicted individuals and does not reverse the biochemical changes that occur in the central nervous system after repeated nicotine use. Endocannabinoid (eCB) signaling has been implicated in modulating the induction and expression of reward-related behaviors for nicotine and nearly all other known drugs of abuse, yet our understanding of the roles of specific eCBs that are involved in nicotine reward remains unclear. Interestingly, combined inhibition of monoacylglycerol lipase (MAGL) and fatty acid acyl hydrolase (FAAH), which degrade distinct sets of eCBs, can mimic the classic cannabinoid behaviors caused by tetrahydrocannabinol (THC), whereas inhibiting each pathway alone only causes a unique partial THC-like response. Thus, individual eCBs likely underlie distinct behavioral phenomena, and modulating these pathways may have different therapeutic outcomes. This project will focus on elucidating the specific eCB signaling mechanisms that reinforce nicotine self-administration in rats, as well as the therapeutic potential of FAAH and MAGL inhibition. Aim 1 will evaluate the effect of selective FAAH and MAGL inhibitors on nicotine self-administration. Aim 2 will characterize eCB changes induced by nicotine self-administration. Using this information, Aim 3 will investigate the receptor mechanisms through which eCBs modulate nicotine self-administration. The overall goal of the experiments described here is to characterize eCB-receptor mechanisms reinforcing nicotine behavior, as well as the effects of eCB clearance inhibition (FAAH and MAGL) on nicotine self- administration behavior. A better understanding of these processes should lead to innovative therapies that have direct impact and clinical relevance for reducing nicotine use in addicted individuals. PUBLIC HEALTH RELEVANCE: The use of tobacco products, driven by the psychoactive effects of nicotine, is one of leading causes of preventable death worldwide. Current treatment options diminish the nicotine withdrawal symptoms that occur in addicted individuals, but do not address the biochemical changes that arise in the brain after chronic nicotine use. The goal of this study is to elucidate the role of endocannabinoids and related bioactive lipids that are affected by chronic nicotine intake to facilitate the development of new therapeutic targets for treating nicotine abuse.

描述（由申请人提供）：使用烟草产品是全球可预防死亡的主要原因之一。烟草的精神活性主要归因于其生物活性物质尼古丁的含量。当前的疗法会减少戒断尼古丁摄入后，在上瘾的个体中出现的戒断症状。但是，这种方法在减少上瘾个体的复发方面仅具有适度的成功率，并且在重复使用尼古丁后，中枢神经系统中发生的生化变化不会扭转。内源性大麻素（ECB）信号传导与调节尼古丁和几乎所有其他已知的滥用药物的奖励相关行为的诱导和表达有关，但是我们对涉及尼古丁奖励的特定ECB的作用的理解尚不清楚。有趣的是，联合抑制了单酰基甘油脂肪酶（MAGL）和脂肪酸酰基水解酶（FAAH），它们可以模仿由四氢甲酰基替诺酚（THC）引起的经典大麻素行为，而单独抑制每种途径仅会导致独特的部分响应。因此，各个ECB可能是不同的行为现象的基础，调节这些途径可能具有不同的治疗结果。该项目将着重于阐明增强大鼠尼古丁自我给药的特定欧洲央行信号传导机制，以及法族和磁抑制的治疗潜力。 AIM 1将评估选择性FAAH和MAGL抑制剂对尼古丁自我给药的影响。 AIM 2将表征由尼古丁自我管理引起的欧洲央行变化。使用此信息，AIM 3将研究ECB调节尼古丁自我管理的受体机制。此处描述的实验的总体目标是表征增强尼古丁行为的欧洲央行 - 振动器机制，以及欧洲央行清除抑制（FAAH和MAGL）对尼古丁自我给药行为的影响。对这些过程的更好理解应导致创新的疗法，这些疗法具有直接影响和临床相关性，以减少上瘾的个体中的尼古丁使用。 公共卫生相关性：在尼古丁的心理活性驱动的烟草产品的使用是全球可预防死亡的主要原因之一。当前的治疗方案减少了上瘾个体中发生的尼古丁戒断症状，​​但不能解决使用慢性尼古丁后大脑中发生的生化变化。这项研究的目的是阐明受慢性尼古丁摄入影响的内源性大麻素和相关生物活性脂质的作用，以促进开发用于治疗尼古丁滥用的新治疗靶标。