The Rodent Electronic Nicotine Delivery System (RENDS): Behavior, physiology, and epigenetics

啮齿动物电子尼古丁输送系统 (RENDS)：行为、生理学和表观遗传学

• 批准号: 10588898
• 负责人: AMY ODUM
• 金额: $ 21.51万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588898
• 关键词: Address; Animals; Area; Award; Basic Science; Behavior; Biological; Blood; Brain; Cause of Death; Cigarette; Complex; Cotinine; Data; Data Analyses; Deposition; Development; Dose; Drug usage; Electronic Nicotine Delivery Systems; Electronic cigarette; Enhancers; Epigenetic Process; Experimental Designs; Exposure to; Extinction; Face; Female; Flavoring; Fruit; Goals; Health; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Inhalation; Injections; Intake; Investigation; Maintenance; Malignant Neoplasms; Measures; Methods; Modeling; Modification; Nicotine; Nicotine Dependence; Nose; Persons; Pharmaceutical Preparations; Phase; Physiological; Physiology; Play; Policies; Population; Pre-Clinical Model; Prevention; Psychological reinforcement; Publications; Rattus; Regimen; Relapse; Reproducibility; Research; Rewards; Rodent; Rodent Model; Role; Self Administration; Smoking; Sodium Butyrate; Sodium Chloride; Time; Tobacco; Tobacco smoking behavior; Tobacco use; Training; Validation; Withdrawal; Woman; Youth; addiction; biological sex; cardiovascular health; cost; drug misuse; drug of abuse; electronic cigarette use; electronic liquid; experience; experimental analysis; health disparity; improved; innovation; male; nicotine treatment; nicotine use; nicotine vapor; novel; novel strategies; open source; pre-clinical; pre-clinical research; prevent; preventable death; public repository; reinforcer; respiratory health; sex; therapy development; uptake; vaping; vaping nicotine; vapor; young adult

Abstract Tobacco smoking is the number one preventable cause of death, causing a myriad of health problems. The primary compound responsible for tobacco use is nicotine. Although nicotine use had been on the decline, it is increasing recently with the rise of electronic nicotine delivery system (ENDS or e-cigarette) use, particularly in youth and young adults. Nicotine in ENDS can make young people more likely to use combusted tobacco cigarettes as well as use drugs of abuse, and cause persistent changes in brain development. Furthermore, women become dependent on nicotine more quickly and have a harder time quitting. Pre-clinical models are critical to examine the complex factors that can impact nicotine uptake and relapse. Current pre-clinical models of rodent electronic cigarette use have multiple limitations, however, including use of the whole-body exposure vapor chamber method, which coats the rodent in the e-liquid and nicotine solution and confounds measures of intake and physiological impact, and extended non-voluntary exposure to vapor while the chamber is cleared. With our Rodent ENDS (RENDS), rats can voluntarily access flavored vapor through a special nose port, thus exposing only the snout of the animal and only for the exact duration the rat chooses. Aim 1 will focus on acquisition and maintenance of RENDS use with young adult rats by examining 1) self-administration 2) cotinine (nicotine metabolite) blood levels and 3) somatic withdrawal across different nicotine doses. The involvement of A) epigenetic modifications during acquisition and maintenance will be preliminarily examined by systemic injection of the histone deacetylase (HDAC) inhibiter sodium butyrate (NaB), which impacts epigenetic processes. To isolate the roles of B) nicotine and fruit flavor, rats will self-administer a) nicotine salt without added flavor, b) fruit flavor without added nicotine, or c) nicotine salt + fruit flavor. Both male and female rats will be studied to examine the influence of C) biological sex. Aim 2 will focus on the cessation and relapse of RENDS use with young adult rats by examining 1) self- administration 2) cotinine blood levels and 3) somatic withdrawal during acquisition, extinction, and reinstatement by systemic injection of nicotine. We will investigate the involvement of A) epigenetic modifications during extinction and reinstatement (relapse) by nicotine and isolate the roles of B) nicotine and flavor and C) biological sex. We suggest that robust self-administration of flavored nicotine reflects nicotine's dual reinforcing actions: nicotine serves as a primary reward, and in addition, increases the reward value of the flavored vapor. We hypothesize that nicotine will serve as a reinforcer as well as reward enhancer in the RENDS. Furthermore, we expect to show that RENDS use results in meaningful cotinine levels, somatic withdrawal, and will be blocked by histone deacetylase inhibition (epigenetic modification). This R21 CEBRA proposal will validate the RENDS to increase the accessibility and scope of research into nicotine reinforcement in rodents as well as begin an investigation into the role of biological sex, fruit flavor, and epigenetic modification in the reinforcing effects of nicotine. These findings may ultimately influence the development of therapies, medications, and policies to prevent and treat ENDS addiction and thus improve human health. Our long-term goal is to elucidate and mitigate the role of epigenetics in nicotine taking and relapse.

摘要 吸烟是头号可预防的死亡原因，会导致无数健康问题。主 导致烟草使用的化合物是尼古丁。虽然尼古丁的使用一直在下降，但最近正在增加 随着电子尼古丁输送系统（ENDS或电子烟）使用的增加，特别是在青年和年轻人中。 ENDS中的尼古丁会使年轻人更有可能使用燃烧的烟草香烟以及滥用药物， 并导致大脑发育的持续变化。此外，女性对尼古丁的依赖更快， 更难戒掉临床前模型对于检查可能影响尼古丁摄取的复杂因素至关重要 和复发然而，目前啮齿动物电子烟使用的临床前模型具有多种局限性，包括 使用全身暴露蒸汽室方法，将啮齿动物涂在电子液体和尼古丁溶液中， 混淆了摄入量和生理影响的测量，并且当腔室 都没问题有了我们的啮齿动物末端（RENDS），老鼠可以通过一个特殊的鼻口自愿获得调味蒸汽， 只暴露动物的鼻子，并且只暴露大鼠选择的确切时间。Aim 1将专注于收购 通过检查1）自我给药2）可替宁（尼古丁）， 代谢物）血液水平和3）不同尼古丁剂量的躯体戒断。A）表观遗传学的参与 在获得和维持期间的修饰将通过系统注射组蛋白来初步检查 脱乙酰酶（HDAC）抑制剂丁酸钠（NaB），其影响表观遗传过程。隔离B的角色） 尼古丁和水果香料，大鼠将自我施用a）尼古丁盐而不添加香料，B）水果香料而不添加香料 尼古丁，或c）尼古丁盐+水果香料。将对雄性和雌性大鼠进行研究，以检查C）的影响 生理性别目的2将通过检查1）自我， 施用2）可替宁血液水平和3）在获得、消退和恢复期间的躯体戒断， 全身注射尼古丁。我们将调查A）灭绝过程中表观遗传修饰的参与， 通过尼古丁恢复（复发），并分离B）尼古丁和香料以及C）生物性别的作用。我们建议 强有力的自我管理的调味尼古丁反映了尼古丁的双重强化作用：尼古丁作为主要的 奖励，并且此外，增加调味蒸汽的奖励值。我们假设尼古丁将作为一种 在RENDS中的奖励增强器。此外，我们希望表明，使用RENDS会导致 有意义的可替宁水平，体细胞戒断，并将被组蛋白脱乙酰酶抑制（表观遗传学）阻断 修改）。该R21 CEBRA提案将验证RENDS，以增加研究的可访问性和范围， 尼古丁在啮齿类动物中的强化作用，以及开始对生物性别、水果风味和 表观遗传修饰在尼古丁的强化作用。这些发现可能最终会影响 治疗，药物和政策，以预防和治疗ENDS成瘾，从而改善人类健康。我们的长期 目的是阐明和减轻表观遗传学在尼古丁服用和复发中的作用。