Establishing Behavioral and Biological Predictors of Problematic Cannabis Use

建立有问题的大麻使用的行为和生物预测因子

• 批准号: 10388270
• 负责人: Ryan Joseph McLaughlin
• 金额: $ 17.85万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388270
• 关键词: Acute; Address; Animal Model; Area; Arousal and Regulatory Systems; Behavior; Behavioral; Behavioral Assay; Biochemical; Biological; Biological Assay; Biological Factors; Biological Markers; Brain; Brain region; CNR1 gene; Cannabis; Cannabis Abuse; Chronic; Classification; Cues; Data; Dependence; Development; Diagnosis; Diagnostic; Diagnostic and Statistical Manual of Mental Disorders; Dimensions; Disease; Dose; Drug usage; Early Diagnosis; Early treatment; Endocannabinoids; Endocrine; Ensure; Etiology; Exhibits; FDA approved; Female; Genes; Goals; Human; Hydrolysis; Impulsivity; Individual; Individual Differences; Intervention; Knowledge; Lead; Left; Lung; Marijuana Dependence; Measures; Metabolic; Modeling; National Institute of Mental Health; Neurobiology; Pathway interactions; Pattern; Persons; Pharmacotherapy; Phenotype; Plasma; Population; Positive Valence; Pre-Clinical Model; Predictive Factor; Rattus; Research Domain Criteria; Rewards; Risk; Route; Self Administration; Single Nucleotide Polymorphism; Statistical Models; Testing; Time; Training; addiction; anandamide; base; brain tissue; density; direct application; disease classification; early detection biomarkers; effective intervention; endocannabinoid signaling; endogenous cannabinoid system; endophenotype; improved; insight; male; marijuana legalization; marijuana use; marijuana use disorder; marijuana user; neurobiological mechanism; novel; pre-clinical; preference; receptor binding; response; sex; trait; trend; vapor

PROJECT SUMMARY The recent wave of recreational cannabis legalization in the US has left many concerned that rates of cannabis dependence and cannabis use disorder (CUD) will rise dramatically in the coming years. Approximately 9% of first-time users will become dependent on cannabis, yet there are no FDA-approved pharmacotherapies for managing CUD. This is in part due to flawed diagnostic nosology resulting in a lack of understanding of the mechanisms that give rise to CUD, as well as a conspicuous lack of translationally relevant animal models of cannabis use. To address these gaps in knowledge, we have developed and validated a novel model of cannabis self-administration that delivers vaporized cannabis extracts in a response-contingent manner via the pulmonary route of administration that is most common among human users. Our data indicate that rats exhibit stable rates of responding for cannabis vapor that produce dose-dependent elevations in plasma Δ9-tetrahydocannabinol (THC) concentrations and metabolic alterations that are consistent with observations in human cannabis users. We will use this model in the proposed studies to identify behavioral and biological factors that predict high vs. low rates cannabis-seeking behavior and subsequently determine region-specific alterations in the endocannabinoid (ECB) system following vapor self-administration. To accomplish this goal, we will conduct a battery of behavioral assays in male and female rats prior to vapor self-administration training. In Aim 1, we will rigorously characterize the phenotype of rats using the National Institute of Mental Health Research Domain Criteria (RDoC) and then determine which behavioral dimensions are most strongly associated with high vs. low responding for cannabis vapor in our model. Given that the endocannabinoid (ECB) system is the primary target for cannabis and is fundamentally involved in the reinforcing effects of THC, in Aim 2 we will test whether circulating endocannabinoid (ECB) tone is a biomarker of a high-responding phenotype. Finally, given that alterations in ECB degradation have been associated with an exaggerated subjective response to the acute effects of cannabis and increased problematic drug use, we will next examine whether cannabis self- administration causes alterations in ECB hydrolysis and CB1 receptor binding in reward-relevant brain regions. We predict that measures of positive valence and arousal/regulatory systems will be the best predictors of individual rates of cannabis self-administration, and that circulating anandamide concentration will be positively associated with cannabis-seeking behavior. We further predict that anandamide degradation and CB1 receptor binding will be decreased in the mesolimbic pathway of high-responding rats following cannabis self- administration. Together, these studies will establish behavioral and biological predictors of problematic cannabis use, which can be leveraged to improve early diagnosis of CUD. These data will also help to identify more efficacious pharmacotherapeutic interventions that are grounded in the neurobiological underpinnings of the disorder, with direct application to human populations afflicted with CUD.

项目摘要 美国最近在美国的娱乐大麻合法化浪潮使许多人担心大麻的比率 在未来几年中，依赖和大麻使用障碍（CUD）将急剧上升。大约9％ 首次用户将依赖大麻，但没有FDA批准的药物治疗 管理Cud。这部分是由于缺陷的诊断性疾病，导致对 引起CUD的机制，以及明显缺乏翻译相关的动物模型 大麻使用。为了解决知识中的这些差距，我们已经开发了并验证了一种新颖的大麻模型 通过肺部以响应方式提供蒸发大麻提取物的自我管理 在人类用户中最常见的管理途径。我们的数据表明大鼠表现稳定 在血浆中产生剂量依赖性高程的大麻蒸气的响应 （THC）与人类大麻使用者的观察结果一致的浓度和代谢改变。 我们将在拟议的研究中使用该模型来识别预测高V的行为和生物学因素。 低比率寻求大麻的行为，随后确定了区域特定的变化 蒸气自我给药后的内源性大麻素（欧洲央行）系统。为了实现这一目标，我们将进行 在进行蒸气自我管理训练之前，男性和雌性大鼠的行为测定。在AIM 1中，我们将 严格地使用国家心理健康研究所的大鼠表型来表征大鼠的表型 标准（RDOC），然后确定哪些行为维度与高与低相关 在我们的模型中响应大麻蒸气。鉴于内源性大麻素（ECB）系统是主要目标 对于大麻，从根本上参与了THC的增强作用，在AIM 2中，我们将测试是否是否 循环内源性大麻素（ECB）音调是高响应表型的生物标志物。最后，鉴于这一点 欧洲央行降解的改变与对急性的主观反应有关 大麻的影响和增加有问题的药物使用的影响，我们将下一步检查大麻自我 给药会导致与奖励相关的大脑区域中欧洲央行水解和CB1受体结合的改变。 我们预测，正价和唤醒/调节系统的衡量标准将是最佳预测指标 大麻自我给药的个体比率，并且循环的anandamide浓度将是积极的 与寻求大麻的行为有关。我们进一步预测，anandamide降解和CB1接收器 大麻自我的高响应大鼠的中唇途径将改善结合 行政。这些研究将共同​​建立问题大麻的行为和生物学预测因子 使用，可以利用以改善CUD的早期诊断。这些数据还将有助于识别更多 天才的药物治疗干预措施，基于神经生物学的基础 疾病，直接应用于患有CUD的人群。