CB1 Mediation of Cerebellum Versus Forebrain-Dependent Associative Learning

描述（由申请人提供）：大麻，或大麻，是美国最常用的非法药物。青少年和青年时期的使用水平增加，从公共卫生的角度来看，这是令人关切的，因为这些时期也是神经发育的关键时期。尤其令人不安的是，每天有6000多名首次吸食大麻的人，其中62.2%的人年龄在18岁以下。由于大麻的使用可能使个人易于滥用其他非法药物，大麻可能成为入门毒品，这一事实进一步强调了这种担忧。此外，大麻的效力（δ -9-四氢大麻酚（¿9-THC）的浓度）现在在美国超过10%（与1983年的4%相比），这可能对正常的大脑功能产生不可预见的后果。考虑到大量的人定期吸食大麻，彻底了解与其行为和生理影响相关的神经机制是相当相关的。小脑可以说是大脑中CB1受体密度最高的区域。众所周知，9-THC会导致短期记忆和注意力等认知功能异常，但外源性大麻素对联想学习的影响却缺乏数据，尤其是与小脑与前脑依赖的经典眨眼条件反射（EBC）相关的数据。我们小组的早期工作表明，在人类中，慢性大麻使用改变了小脑依赖性延迟EBC的条件反应（CR）获取和时间，但在前脑依赖性痕量EBC任务中没有改变。然而，目前尚不清楚，在慢性大麻使用者中观察到的缺陷是由于¿9-四氢大麻酚、大麻中存在的其他大麻素、CB1下调的残留效应，还是吸毒个体的发病前差异。因此，当前应用的总体目标是研究急性，iv - THC给药是否分别通过延迟和痕量EBC评估人类小脑与前脑依赖的联想学习。基于已知的CB1在小脑中的作用，假设的结果是：与安慰剂相比，9-THC会以剂量依赖的方式诱导小脑依赖性延迟性EBC的损伤（降低CR百分比和改变CR潜伏期）。预计¿9-THC对前脑依赖性痕量EBC的影响很小或没有影响。综上所述，希望这些研究的数据将进一步加深我们对大麻素系统的理解，特别是在联想学习的背景下，这将有助于阐明最常用的滥用药物之一的作用机制。

DESCRIPTION (provided by applicant): Marijuana, or Cannabis sativa, is the most commonly used illicit drug in the United States. Increased levels of use occur during adolescence and young adulthood, which is of concern from a public health perspective, since these are also critical periods of neural development. What is particularly disturbing is the fact that there are over 6000 first-time cannabis users added per day, 62.2 percent of which are under the age of eighteen. This fear is further underscored by the fact that cannabis may act as a gateway drug, since its use may predispose individuals to abuse other illicit drugs. Further, the potency of cannabis (concentration of delta-9- tetrahydrocannabinol (¿9-THC)), is now exceeding 10 percent in the U.S. (compared to 4 percent in 1983), which could have unforeseen consequences for normal brain function. Given the vast number of individuals who consume cannabis on a regular basis, a thorough understanding of the neural mechanisms associated with its behavioral and physiological effects are of considerable relevance. The cerebellum arguably contains the highest density of CB1 receptors in the brain. While it is well known that ¿9-THC causes abnormalities in cognitive functions such as short-term memory and attention, there are a paucity of data examining the effect of exogenous cannabinoids on associative learning, particularly as it relates to cerebellar versus forebrain-dependent classical eyeblink conditioning (EBC). Earlier work from our group has shown that in humans, chronic cannabis use alters conditioned response (CR) acquisition and timing in cerebellar-dependent delay EBC, but not in the forebrain-dependent trace EBC task. However, it remains unclear whether the deficits observed in chronic cannabis users are due to the residual effects of ¿9- THC, some other cannabinoid present in cannabis, CB1 downregulation, or premorbid differences in drug- seeking individuals. Therefore, the overall aim of the current application is to investigate whether acute, i.v. ¿9- THC administration mediates cerebellum- versus forebrain-dependent associative learning in humans as assessed with delay and trace EBC, respectively. The hypothesized outcome, based on known CB1 actions in the cerebellum, is that ¿9-THC (as compared to placebo) will induce impairments in cerebellar dependent delay EBC in a dose-dependent manner (decreased percent CRs and altered CR latency). It is also expected that ¿9-THC will have little or no effect on forebrain-dependent trace EBC. Taken together, it is hoped that data from these studies will further our understanding of the cannabinoid system, particularly in the context of associative learning, which will help elucidate the mechanism of action of one of the most commonly used drugs of abuse. PUBLIC HEALTH RELEVANCE: The public health relevance of this application can be summarized as follows: 1) Cannabis exposure likely produces neural changes in the endogenous cannabinoid system, and the effect of such changes on information processing within the brain is unclear. 2) Understanding how the active ingredient in cannabis (Delta-9-THC) interacts with the neural substrates underlying information processing will improve care and prevention of cannabis abuse/dependence. 3) The proposed study has a high potential for future translational research, as the eyeblink conditioning task is widely employed in animal studies, and the neural circuitry mediating this task is well conserved across species (i.e. result from the current studies will be testable in future animal models of cannabinoid function).