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

描述（由申请人提供）：人类长期使用大麻与一系列情感、认知和神经改变有关，包括抑郁和焦虑的发生率较高、记忆和执行功能缺陷以及脑容量和白色完整性的区域减少。新出现的证据表明，当大麻使用开始于幼年时，这些变化更大，并且可以持续到禁欲，这表明青少年大麻暴露可能对发育中的大脑产生特别有害的影响。这些发现与啮齿动物模型中的研究一致，表明在青春期给予9 THC或其他大麻素激动剂会导致认知缺陷和成年后的负面影响增加。然而，值得注意的是，几乎没有关于青少年暴露于大麻烟雾对神经行为结果影响的研究。缺乏这样的研究是惊人的，不仅因为吸烟是人类使用大麻的首选途径，而且因为大麻烟雾含有大量大麻素和除9 THC之外的其他化合物，其中一些已知是精神活性的，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，必须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于大麻烟雾如何影响成年人的情绪，认知和大脑结构/功能措施，这些措施在人类大麻使用者中显示出改变。对于这一长期目标很重要，我们已经在大鼠中建立了大麻烟雾暴露模型，该模型产生的血液THC水平与人类中发现的水平相当，并且我们已经证明了慢性暴露后的大麻依赖性。基于这些初步数据，以及已发表的关于大麻使用者的文献，我们的中心假设是，青少年大麻烟雾暴露将对成年后的情绪和认知过程造成有害影响，并伴有相关脑回路的结构异常。我们将在大鼠模型中测试这一中心假设：1）确定青少年大麻烟雾暴露是否会影响负面影响（抑郁和焦虑样行为的措施）在成年期; 2）确定青少年大麻烟雾暴露是否影响成年期记忆和执行功能的多项措施; 3）使用与评估人类大麻使用者所采用的类似的神经成像技术，确定青少年大麻烟雾暴露是否影响成年期的脑容量和白色物质完整性。除了为医疗和公共政策决策提供信息外，该项目的研究结果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性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.