Establishing Behavioral and Biological Predictors of Problematic Cannabis Use

项目摘要 最近美国娱乐性大麻合法化的浪潮让许多人担心大麻的使用率 大麻依赖和大麻使用障碍（CUD）将在未来几年急剧上升。大约9%的 首次使用者将依赖大麻，但没有FDA批准的药物治疗 管理CUD。这部分是由于有缺陷的诊断疾病分类学导致缺乏对疾病的了解。 引起CUD的机制，以及明显缺乏预防相关的动物模型， 使用大麻为了解决这些知识差距，我们开发并验证了一种新的大麻模型 通过肺部以响应视情况而定的方式递送汽化的大麻提取物的自我给药 给药途径是人类用户中最常见的。我们的数据表明老鼠表现出稳定的 对大麻蒸汽产生剂量依赖性血浆Δ9-四氢大麻酚升高的反应 (THC)这些结果表明，大麻的浓度和代谢变化与人类大麻使用者的观察结果一致。 我们将在拟议的研究中使用该模型来确定预测高vs. 低利率大麻寻求行为，并随后确定特定区域的变化， 内源性大麻素（ECB）系统的蒸汽自我管理。为了实现这一目标，我们将开展一项 在蒸汽自我给药训练之前，在雄性和雌性大鼠中进行一系列行为测定。在目标1中，我们 使用国家精神卫生研究所研究领域严格描述大鼠的表型 标准（RDoC），然后确定哪些行为维度与高与低 对大麻蒸汽的反应由于内源性大麻素（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，我们将测试是否 循环内源性大麻素（ECB）张力是高应答表型的生物标志物。最后，鉴于 欧洲央行降级的变化与对急性危机的夸大主观反应有关。 大麻的影响和问题药物使用的增加，我们接下来将研究大麻是否自我- 给药引起ECB水解和CB 1受体结合在奖励相关的脑区域的改变。 我们预测，积极效价和唤醒/调节系统的措施将是最好的预测， 大麻自我管理的个人比率，以及循环anandamide浓度将是积极的 与寻求大麻的行为有关。我们进一步预测大麻素的降解和CB 1受体 大麻自我释放后，高反应大鼠的中脑边缘通路中的结合将减少。 局总之，这些研究将建立问题大麻的行为和生物学预测 使用，这可以用来改善CUD的早期诊断。这些数据也将有助于确定更多 有效的药物干预，是在神经生物学基础的基础上， 疾病，直接应用于患有CUD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.