Establishing Behavioral and Biological Predictors of Problematic Cannabis Use

点击翻译按钮获取中文摘要

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.