Establishing Behavioral and Biological Predictors of Problematic Cannabis Use

项目总结 最近美国娱乐性大麻合法化的浪潮让许多人担心大麻的比率 依赖和大麻使用障碍(CUD)将在未来几年急剧上升。约9%的 第一次吸食大麻的人会对大麻产生依赖，但目前还没有FDA批准的药物疗法来治疗 管理CUD。这在一定程度上是由于诊断病因学存在缺陷，导致对 导致CUD的机制，以及明显缺乏翻译上相关的动物模型 吸食大麻。为了解决这些知识上的差距，我们开发并验证了一种新的大麻模型 通过肺脏以应答性方式递送蒸发大麻提取物的自我给药 在人类用户中最常见的管理路径。我们的数据表明，老鼠表现出稳定的比率 对大麻蒸气引起血浆Δ9-四氢大麻酚剂量依赖性升高的反应 (THC)浓度和代谢变化与在人类大麻使用者中观察到的一致。 我们将在拟议的研究中使用该模型来确定预测高血压与 低比率的大麻寻找行为，并随后确定区域特有的改变 蒸汽自我给药后的内源性大麻(ECB)系统。为了实现这一目标，我们将进行一项 蒸气自我给药训练前雄性和雌性大鼠的行为分析。在目标1中，我们将 使用国家精神卫生研究领域研究所严格表征大鼠的表型 标准(RDoC)，然后确定哪些行为维度与高与低的关联最强 在我们的模型中是对大麻蒸气的反应。鉴于内源性大麻素(ECB)系统是主要目标 对于大麻，并从根本上参与THC的强化作用，在目标2中，我们将测试 循环内大麻素(ECB)是一种高反应表型的生物标志物。最后，鉴于 欧洲央行降级的变化与对急性金融危机的夸大主观反应有关 大麻的影响和更多有问题的药物使用，我们接下来将检查大麻本身是否 给药导致奖赏相关脑区ECB的水解和CB1受体结合的改变。 我们预测，正价和唤醒/调节系统的测量将是最好的预测因子 个人服用大麻的比率，以及循环中的阿南达胺浓度将为正值 与寻找大麻的行为有关。我们进一步预测花生胺降解和CB1受体 高反应性大鼠自身吸食大麻后中脑边缘通路的结合减少 行政管理。总之，这些研究将建立有问题的大麻的行为和生物学预测指标 使用，这可以被用来提高CUD的早期诊断。这些数据还将有助于识别更多 基于神经生物学基础的有效药物治疗干预措施 混乱，直接适用于患有慢性阻塞性肺病的人群。

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.