Effect of nicotine self-administration on endocannabinoids & related lipids

描述（由申请人提供）：烟草制品的使用是全球可预防死亡的主要原因之一。烟草的精神作用主要归因于其生物活性物质尼古丁的含量。目前的疗法减少了成瘾个体在停止尼古丁摄入后出现的戒断症状。然而，这种方法在减少成瘾个体的复发方面只有中等的成功率，并且不能逆转重复使用尼古丁后中枢神经系统中发生的生化变化。内源性大麻素（eCB）信号转导参与调节尼古丁和几乎所有其他已知滥用药物的奖励相关行为的诱导和表达，但我们对尼古丁奖励中涉及的特定eCB的作用的理解仍不清楚。有趣的是，单酰基甘油脂酶（MAGL）和脂肪酸酰基水解酶（FAAH）的联合抑制，降解不同的eCB组，可以模拟由四氢大麻酚（THC）引起的经典大麻素行为，而单独抑制每种途径只会引起独特的部分THC样反应。因此，个体eCB可能是不同行为现象的基础，调节这些途径可能具有不同的治疗结果。该项目将重点阐明增强大鼠尼古丁自我给药的特定eCB信号传导机制，以及FAAH和MAGL抑制的治疗潜力。目的1将评估选择性FAAH和MAGL抑制剂对尼古丁自我给药的影响。目的2将描述尼古丁自我给药诱导的eCB变化。利用这些信息，目标3将研究eCB调节尼古丁自我给药的受体机制。本文所述实验的总体目标是表征增强尼古丁行为的eCB受体机制以及eCB清除抑制（FAAH和MAGL）对尼古丁自我给药行为的影响。更好地了解这些过程应该会导致创新疗法，这些疗法对减少成瘾者的尼古丁使用具有直接影响和临床意义。 公共卫生相关性：烟草制品的使用是由尼古丁的精神作用驱动的，是全球可预防死亡的主要原因之一。目前的治疗方案减少了成瘾者的尼古丁戒断症状，但没有解决长期使用尼古丁后大脑中出现的生化变化。本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，以促进治疗尼古丁滥用的新治疗靶点的开发。

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.