Lasting behavioral and neuroimaging consequences of adolescent exposure to cannabis smoke.

描述(申请人提供)：人类长期使用大麻与一系列情感、认知和神经改变有关，包括更高的抑郁和焦虑发生率，记忆和执行功能障碍，以及脑体积和白质完整性的区域性减少。新出现的证据表明，在很小的时候就开始使用大麻，这些变化会更大，并可以持续到戒烟，这表明青少年接触大麻可能对发育中的大脑产生特别有害的影响。这些发现与对啮齿动物模型的研究一致，该研究表明，在青春期服用9THC或其他大麻类激动剂会导致认知障碍，并在成年后增加负面影响。然而，值得注意的是，几乎没有关于青少年暴露在大麻烟雾中对神经行为结果的影响的研究。这种研究的缺乏是令人震惊的，不仅因为吸烟是人类使用大麻的首选途径，而且因为大麻烟雾中除了9THC之外还含有许多大麻素和其他化合物，其中一些已知具有精神活性，可能对大脑和行为产生持久影响。因此，为了评估大麻使用的因果影响，至关重要的是采用模拟人类实际接触条件的模型。这项研究计划的长期目标是确定青少年暴露在大麻烟雾中如何影响成人的情感、认知和大脑结构/功能指标，这些指标在人类大麻使用者中被证明是改变的。对于这一长期目标来说，我们已经建立了一种大鼠大麻烟雾暴露模型，该模型产生的血液THC水平与在人类中发现的水平相当，在该模型中，我们在长期暴露后表现出对大麻的依赖。根据这些初步数据以及已发表的有关大麻使用者的文献，我们的中心假设是，青少年吸食大麻会对成年后的情绪和认知过程造成有害影响，并伴随着相关大脑回路的结构性异常。我们将在老鼠模型中测试这一中心假说：1)确定青少年吸烟是否会影响成年期的负面情绪(抑郁和焦虑样行为的衡量标准)；2)确定青少年吸烟是否会影响成年后记忆和执行功能的多项衡量标准；3)使用类似于评估人类大麻使用者的神经成像技术，确定青少年吸烟是否会影响成年期的脑容量和脑白质完整性。除了为医疗和公共政策决策提供信息外，该项目的发现还将为更广泛的研究计划奠定基础，该研究计划旨在了解发育中的大麻烟雾暴露影响大脑和行为的机制。

DESCRIPTION (provided by applicant): Chronic cannabis use in humans is associated with a range of affective, cognitive, and neural alterations, including a higher incidence of depression and anxiety, deficits in memory and executive functions, and regional reductions in brain volume and white matter integrity. Emerging evidence indicates that these alterations are greater when cannabis use begins at an early age and can persist well into abstinence, indicating that adolescent cannabis exposure may have particularly deleterious effects on the developing brain. These findings are consistent with research in rodent models showing that administration of ¿9THC or other cannabinoid agonists during adolescence causes cognitive deficits and increased negative affect in adulthood. Notably, however, there is almost no research on the effects of adolescent exposure to cannabis smoke on neurobehavioral outcomes. The lack of such research is striking, not only because smoking is the preferred route of human cannabis use, but because cannabis smoke contains numerous cannabinoid and other compounds aside from ¿9THC, some of which are known to be psychoactive and may have lasting effects on the brain and behavior. Hence, in order to assess the causal impact of cannabis use, it is critical to employ a model that mimics the conditions of actual human exposure. The long-term goal of this research program is to determine how adolescent exposure to cannabis smoke affects adult emotional, cognitive, and brain structural/functional measures shown to be altered in human cannabis users. Important to this long-term goal, we have established a cannabis smoke exposure model in rats, which produces blood THC levels comparable to those found in humans and in which we have demonstrated cannabis dependence following chronic exposure. Building on these preliminary data, as well as published literature on cannabis users, our central hypothesis is that adolescent cannabis smoke exposure will cause deleterious effects on emotional and cognitive processing in adulthood that are accompanied by structural abnormalities in relevant brain circuitry. We will test this central hypothesis in a rat model by: 1) determining whether adolescent cannabis smoke exposure influences negative affect (measures of depression- and anxiety-like behavior) during adulthood; 2) determining whether adolescent cannabis smoke exposure influences multiple measures of memory and executive function in adulthood; 3) determining whether adolescent cannabis smoke exposure affects brain volume and white matter integrity during adulthood, using neuroimaging techniques similar to those employed in assessments of human cannabis users. In addition to informing medical and public policy decision making, findings from this project will lay the groundwork for a broader research program directed toward understanding the mechanisms by which developmental cannabis smoke exposure affects the brain and behavior.