ICAL: Impact of Cannabinoids Across Lifespan: Molecular Project

ICAL：大麻素对整个生命周期的影响：分子项目

• 批准号: 10188478
• 负责人: Daniele Piomelli
• 金额: $ 42.65万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188478
• 关键词: 2-arachidonylglycerol; Acute; Adolescence; Adolescent; Adult; Affect; Age; Animal Experiments; Animals; Behavior; Behavioral; Biochemical; Brain; CNR1 gene; Cannabinoids; Cognition; Collaborations; Complex; Data Set; Dependence; Development; Dopamine; Down-Regulation; Endocannabinoids; Ensure; Epigenetic Process; Episodic memory; Exposure to; Foundations; Future; Gene-Modified; Genes; Genetic; Glutamates; Health; Hippocampus (Brain); Impairment; In Vitro; Injections; Knowledge; Lipids; Long-Term Effects; Longevity; Maintenance; Mediating; Memory; Modification; Molecular; Motivation; Mus; Neural Pathways; Nucleus Accumbens; Outcome; Pharmaceutical Preparations; Prefrontal Cortex; Prospective Studies; Proteins; Protocols documentation; Rattus; Regimen; Regulation; Research Activity; Rewards; Stimulus; Synapses; Synaptosomes; System; THC exposure; Teenagers; Testing; Tetrahydrocannabinol; United States National Institutes of Health; adolescent substance use; cannabinoid receptor; cognitive development; dentate gyrus; design; drug reward; endocannabinoid signaling; endogenous cannabinoid system; entorhinal cortex; gain of function; gene product; genetic manipulation; histone modification; in vivo; loss of function; marijuana use; mature animal; middle age; neurobehavioral; organizational structure; postnatal; predictive marker; recruit; sex; spatial memory; synergism

MOLECULAR PROJECT: SUMMARY Adolescent administration of Δ9-tetrahydrocannabinol (THC) causes long-lasting neurobehavioral impairments in mice and rats. The Molecular Project will test the hypothesis that these enduring effects result from excessive activation of CB1-type cannabinoid receptor (CB1R), which triggers epigenetic processes resulting in region- and circuit-specific down-regulation of endocannabinoid (ECB) signaling. We have two specific aims. In Aim 1, we will examine whether acute or prolonged exposure to THC during adolescence alters molecular components of the ECB system, and/or the ability of this system to be engaged by environmental stimuli. We will test, in mice and rats of both sexes, acute and prolonged THC regimens designed to mimic occasional or daily cannabis use in teenagers. Outcomes will be assessed at three stages of the animals’ lifespan: end of treatment (24 h after last THC injection), adulthood (postnatal day, PND 70) and middle age (PND 300). To determine the age-dependence of the effects of THC, adult animals (PND 70) will be subjected to an identical protocol. We will determine the effects of acute or prolonged adolescent THC exposure on (i) lipid, protein and gene constituents of the ECB complex; (ii) epigenetic modifications; and (iii) stimulus- dependent ECB signaling in vitro and in vivo. Aim 2 will identify molecular mechanisms responsible for the induction and maintenance of persistent cannabinoid-dependent alterations in ECB signaling. Focusing on the prolonged THC protocol – which we expect will have the strongest impact on ECB system, synaptic activity and behavior – we will use loss-of-function and/or gain-of-function strategies to define the CBR subtype(s) mediating the long-lasting effects of adolescent THC treatment; and describe epigenetic and biochemical mechanisms potentially responsible for the transition to persistent changes in ECB signaling. We anticipate that (i) CB1R, not CB2R, mediates the long-lasting effects of adolescent THC exposure and (ii) genetic manipulations targeting specific genes or histone modifications affected by THC will correct molecular, synaptic and behavioral deficits observed in THC-treated animals. A deep understanding of the enduring actions of THC at the genetic, epigenetic and biochemical level will have several applications: first, it will guide the research activities of all other ICAL projects: second, it will help interpret the datasets generated by prospective studies that assess the long-term health impact of adolescent substance use (e.g, the ABCD study); and, third, it will guide the future discovery of predictive biomarkers of exposure outcomes as well as for the rational development of medications aimed at correcting the neurobehavioral consequences of teenage cannabis use.

分子项目：总结 青少年服用 Δ9-四氢大麻酚 (THC) 会导致长期的神经行为损伤 分子项目将测试这些持久影响是由小鼠和大鼠引起的假设。 CB1型大麻素受体（CB1R）的过度激活，触发表观遗传过程，导致 在内源性大麻素 (ECB) 信号传导的区域和电路特异性下调中，我们有两种特定的方法。 在目标 1 中，我们将研究青春期期间急性或长期接触 THC 是否会改变。 ECB 系统的分子组成部分，和/或该系统受环境影响的能力 我们将在两种性别的小鼠和大鼠中测试旨在模拟的急性和长期 THC 方案。 青少年偶尔或每天使用大麻的结果将在动物的三个阶段进行评估。 寿命：治疗结束（最后一次 THC 注射后 24 小时）、成年期（出生后一天，PND 70）和中年 (PND 300) 为了确定 THC 影响的年龄依赖性，将对成年动物 (PND 70) 进行研究。 我们将确定青少年急性或长期接触 THC 对 (i) 的影响。 ECB 复合物的脂质、蛋白质和基因成分；(ii) 表观遗传修饰；以及 (iii) 刺激- 目标 2 将确定体外和体内依赖的 ECB 信号传导的分子机制。 诱导和维持 ECB 信号传导中持续的大麻素依赖性改变。 延长 THC 协议——我们预计这将对 ECB 系统、突触活动产生最强烈的影响 和行为 – 我们将使用功能丧失和/或功能获得策略来定义 CBR 亚型 调节青少年 THC 治疗的长期影响；并描述表观遗传和生物化学 我们预计，这种机制可能会导致欧洲央行信号持续变化。 (i) CB1R，而不是 CB2R，介导青少年 THC 暴露的长期影响，以及 (ii) 遗传 针对受 THC 影响的特定基因或组蛋白修饰的操作将纠正分子、 在 THC 治疗的动物中观察到的突触和行为缺陷对持久性的深入了解。 THC 在遗传、表观遗传和生化水平上的作用将具有多种应用：首先，它将指导 所有其他 ICAL 项目的研究活动：其次，它将有助于解释由 评估青少年物质使用对健康的长期影响的前瞻性研究（例如 ABCD 研究）；第三，它将指导未来暴露结果的预测生物标志物的发现以及 合理开发旨在纠正神经行为后果的药物 青少年吸食大麻。