Brain-Behavior Markers of Reward and Cannabis Abuse Risk in Young Adults

这项研究的首要目标是获得必要的培训，以更好地理解神经 大麻的奖励和强化特性背后的机制。拟议的研究旨在 表征个体在对Delta-9的主观奖赏反应和神经奖赏加工上的差异 四氢大麻酚(THC)，大麻中的主要精神活性成分，在健康的年轻人中 可能面临使用有问题的大麻的风险。不同个体对自我的主观反应不同 报告毒品奖励的措施。很少有研究研究THC如何影响大脑奖赏回路 人类。随着大麻在美国变得越来越容易获得，人们对大麻的负面影响感到严重担忧 与问题使用相关的结果。为了最大限度地减少增加使用的不利影响，关键是要确定 使某些个人更容易受到有问题的大麻使用的风险因素。其中一个因素牵涉到 药物使用和滥用的风险是大脑奖励回路的敏感性和功能，特别是在对 早期吸毒。初步证据表明，THC激活大脑奖赏回路，特别是腹侧 纹状体(VS)和内侧前额叶皮质(MPFC)，这可能与奖赏的个体差异有关 大麻的影响。到目前为止，人们对奖赏、强化的神经机制知之甚少。 大麻的特性以及这些特性如何导致个体在主观奖励反应上的差异 THC，药物滥用责任的标志。在目前的K23申请中，我建议审查情感奖励 确定可能面临大麻使用和滥用风险的个人的机制。在拟议的研究中，80 健康的年轻人(18-25岁)，报告偶尔吸食大麻(生活中使用≥10倍，但每周使用≤1次)，将 接受两次双盲、受试者内部的药物挑战访问(安慰剂，7.5 mg THC)。在这些访问期间， 参与者将在脑电(EEG)和功能测试期间完成神经奖赏测量 磁共振成像(FMRI)以及药物奖励的主观测量。通过将神经和 行为测量与急性给药设计，我将(A)确定THC是否增强大脑 奖赏反应性；(B)检查THC诱导的神经奖赏反应性改变是否与主观有关 奖赏反应；和(C)确定是否“基线”神经奖赏反应性(即，在安慰剂治疗期间) 预测对THC的主观奖励反应。这项研究同时提供了一个极好的机会 在几个关键领域接受导师指导的实践培训，以完善我的知识和技能- 布景。具体地说，拟议的培训计划将侧重于四个新领域：1)脑电，2)成瘾和毒品 管理学，3)生物统计学，4)职业发展。这项研究，加上完成 的培训目标将开启我在药物翻译情感神经科学领域的独立职业生涯 并将为未来关注行为-大脑风险的高影响R01研究奠定基础 包括大麻使用障碍在内的物质使用障碍的表型和干预目标。

The overarching goal of the study is to obtain the necessary training to better understand the neural mechanisms underlying the rewarding, reinforcing properties of cannabis. The proposed study aims to characterize individual differences in subjective reward response and neural reward processing to delta-9- tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, among healthy young adults who may be at-risk for problematic cannabis use. Individuals differ in their subjective response to THC on self- report measures of drug reward. Few studies have examined how THC impacts brain reward circuitry in humans. As cannabis becomes increasingly available in the U.S. there is serious concern about negative outcomes related to problematic use. To minimize the adverse impact of increased use, it is critical to identify risk factors that make certain individuals more vulnerable to problematic cannabis use. One factor implicated in risk for drug use and abuse is the sensitivity and function of brain reward circuitry, especially in response to early drug use. Preliminary evidence indicates that THC activates brain reward circuitry, especially the ventral striatum (VS) and medial prefrontal cortex (mPFC), which might be linked to individual differences in rewarding effects of cannabis. To date, little is known about the neural mechanisms underlying the rewarding, reinforcing properties of cannabis and how these may contribute to individual differences in subjective reward response to THC, a marker of drug abuse liability. In the current K23 application, I propose to examine the affective reward mechanisms that identify individuals who may be at risk for cannabis use and abuse. In the proposed study, 80 healthy young adults (aged 18-25), who report occasional cannabis use (≥10x in life, but use ≤1x a week), will undergo two double-blind, within-subject, drug-challenge visits (placebo, 7.5mg THC). During these visits, participants will complete neural measures of reward during electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI), as well as subjective measures of drug reward. By combining neural and behavioral measures with an acute drug administration design, I will (a) determine if THC enhances brain reward reactivity; (b) examine if THC-induced alterations in neural reward reactivity are related to subjective reward response; and (c) determine if “baseline” neural reward reactivity (i.e., during the placebo session) predicts subjective reward response to THC. This study concurrently provides an excellent opportunity to receive mentor-directed, hands-on training in several key areas necessary to refine my knowledge and skill- sets. Specifically, the proposed training plan will focus on four new domains: 1) EEG, 2) Addiction and drug administration studies, 3) Biostatistics, and 4) Professional development. This study, coupled with completion of the training goals will launch my independent career in the translational affective neuroscience of drug abuse and will lay the foundation for future, high impact R01 studies focused on behavioral-brain risk phenotypes and intervention targets for Substance Use Disorders, including Cannabis Use Disorder.