Effects of developmental cannabis exposure on prefrontocortical structure and function

项目摘要 大麻是美国最常滥用的非法药物。随着几个州最近通过了 立法允许使用大麻用于娱乐目的，有合理的关注，这可能 大幅度增加大麻在敏感发育人群中的供应和使用。青春期是一个 动态皮质发育期，促进适当的行为和认知成熟，因此， 许多人担心，在这一时期长期使用大麻可能会干扰这些重要的发育， 过程，从而有助于出现认知和/或动机缺陷的成年。临床 研究证实了这一观点;然而，青少年使用大麻的长期因果影响， 很难解释清楚。在这方面，临床前动物模型是有利的，然而，目前的动物模型在这方面是有利的。 大麻暴露一直受到方法问题的困扰，这些问题限制了这些数据的可翻译性， 人类种群。我们的实验室使用一种新颖的、与实验相关的模型生成了重要的新数据。 大鼠自我给予大麻蒸气的研究。这种新方法使用定制设计的设备提供离散的 “喷”的蒸发大麻提取物在响应视情况而定的方式。这种方法的独特之处在于它使用 天然大麻提取物（而不是合成大麻素受体激动剂或分离的大麻成分） 其通过在人类使用者中最常见的肺部给药途径递送。我们将使用这个 确定自我施用汽化大麻提取物的程度的创新方法， 高Δ9-四氢大麻酚（THC）和/或大麻二酚（CBD）会导致皮质中的长期改变， 发展，认知灵活性和基于努力的决策。此外，我们将研究是否有这样的 改变以年龄、性别和/或药物依赖性方式发生。对于目标1，自动设置转换任务将是 用于评估认知灵活性的缺陷，而努力折扣任务将用于评估努力的缺陷- 基于决策。对于目标2，将从目标1中测试的大鼠中收获大脑，以确定是否存在潜在的 任务表现的处理效果与白色物质发育的个体差异有关， 前额叶皮层（PFC）的棘密度。我们的总体假设是，肺内自我给药 四氢大麻酚含量高的提取物会对注意力转移产生长期损害， 更大，更努力的奖励，特别是在自我管理之后。我们进一步预测， 这些认知障碍将与PFC中髓鞘形成和突触修剪的异常相关， 这些长期的认知和结构障碍将在接受等比例的 CBD丰富的提取物。预计这些结果将通过为一个新的技术领域提供概念验证， 一种新的，与肺大麻自我给药相关的模型，并描述其长期 结构性和功能性后果。此外，这项工作将为未来的研究奠定基础， 剖析大麻暴露影响认知，动机和成瘾脆弱性的机制。

Project Summary Cannabis is the most commonly abused illicit drug in the United States. With several states recently passing legislation permitting the use of cannabis for recreational purposes, there is valid concern that this could dramatically increase the availability and use of cannabis in sensitive developmental populations. Adolescence is a period of dynamic cortical development that facilitates proper behavioral and cognitive maturation, and as such, many are worried that chronic cannabis use during this period may interfere with these important developmental processes, thereby contributing to the emergence of cognitive and/or motivational deficits in adulthood. Clinical studies have lent credence to this notion; however, the long-term causal effects of adolescent cannabis use have been difficult to elucidate. Preclinical animal models are advantageous in this respect, yet current models of cannabis exposure have been plagued by methodological concerns that limit the translatability of these data to human populations. Our laboratory has generated important new data using a novel, translationally relevant model of cannabis vapor self-administration in rats. This new method uses custom-designed equipment to deliver discrete ‘puffs’ of vaporized cannabis extracts in a response-contingent manner. This approach is unique in that it uses natural cannabis extracts (rather than synthetic cannabinoid receptor agonists or isolated cannabis constituents) that are delivered via the pulmonary route of administration that is most common in human users. We will use this innovative approach to determine the extent to which self-administration of vaporized cannabis extracts that are high in Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD) elicits long-term alterations in cortical development, cognitive flexibility, and effort-based decision making. Moreover, we will examine whether such alterations occur in an age-, sex-, and/or drug-dependent manner. For Aim 1, an automated set-shifting task will be used to assess deficits in cognitive flexibility, and an effort-discounting task will be used to assess deficits in effort- based decision-making. For Aim 2, brains will be harvested from rats tested in Aim 1 to determine whether potential treatment effects in task performance are associated with individual differences in white matter development and spine density in the prefrontal cortex (PFC). Our overarching hypothesis is that intrapulmonary self-administration of an extract high in THC will produce long-term impairments in attentional set shifting and reduce the preference for larger, more effortful rewards, especially following adolescent-onset self-administration. We further predict that these cognitive impairments will be associated with aberrations in myelination and synaptic pruning in the PFC, and that these long-term cognitive and structural impairments will be attenuated in cohorts receiving an equal ratio of the CBD-rich extract. The results are expected to positively impact the field by providing the proof-of-concept for a novel, translationally relevant model of pulmonary cannabis self-administration and delineating its long-term structural and functional consequences. Additionally, this work will provide the foundation for future studies that will dissect the mechanisms by which cannabis exposure impacts cognition, motivation, and vulnerability for addiction.