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.

抽象的 吸烟是可预防的死亡原因，导致无数健康问题。主要 负责烟草使用的复合是尼古丁。尽管使用尼古丁已经下降，但最近正在增加 随着电子尼古丁输送系统（末端或电子烟）使用的兴起，尤其是在青年和年轻人中。 尼古丁末端可能会使年轻人更有可能使用燃烧的烟草香烟，并使用滥用药物， 并导致大脑发育的持续变化。此外，女性更快地依赖尼古丁，并且 很难退出。临床前模型对于检查可能影响尼古丁吸收的复杂因素至关重要 和复发。但是 使用全身暴露蒸气室法，该方法将啮齿动物覆盖在电子液体和尼古丁溶液中， 混淆了摄入量和生理影响的措施，并扩展了非自愿暴露于蒸气时 被清除。有了我们的啮齿动物末端（渲染），大鼠可以通过特殊的鼻子端口自愿进入调味蒸气，因此 仅暴露动物的鼻子，只有大鼠选择的确切持续时间。 AIM 1将专注于收购 并通过检查年轻大鼠的订单维护1）自我给药2）cotinine（尼古丁 代谢物）血液水平和3）跨不同尼古丁剂量的躯体戒断。 A）表观遗传学的参与 在获取和维护过程中的修改将通过全身注入组蛋白初步检查 脱乙酰基酶（HDAC）抑制剂丁酸钠（NAB），影响表观遗传过程。隔离B的角色） 尼古丁和水果味，大鼠会自我助手a）尼古丁盐而没有添加味道，b）果实味 尼古丁，或C）尼古丁盐 +水果味。将研究雄性和雌性大鼠以检查C的影响） 生物性别。 AIM 2将重点介绍通过检查年轻大鼠使用的订单和复发1）自我 给药2）可替宁的血液水平和3）在获取，灭绝和恢复原处的躯体戒断 尼古丁的全身注入。我们将研究a）灭绝期间表观遗传修饰的参与 通过尼古丁恢复（复发），并隔离B）尼古丁和风味以及c）生物学的作用。我们建议这样做 尼古丁的强大自我服用反映了尼古丁的双重增强作用：尼古丁用作主要 奖励，此外，还增加了调味蒸气的奖励价值。我们假设尼古丁将作为 增强器以及奖励增强剂。此外，我们希望表明使用结果结果 有意义的可替宁水平，躯体戒断，将被组蛋白脱乙酰基酶抑制（表观遗传学）阻塞 修改）。该R21 CEBRA提案将验证这些结果，以将研究的可访问性和范围提高到 啮齿动物中的尼古丁加固，并开始调查生物性，水果风味和 尼古丁增强作用的表观遗传修饰。这些发现最终可能会影响 预防和治疗终点成瘾并从而改善人类健康的疗法，药物和政策。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。