CB1 Mediation of Cerebellum Versus Forebrain-Dependent Associative Learning

描述(申请人提供)：大麻，或大麻，是美国最常用的非法药物。青春期和青春期的使用水平有所增加，从公共卫生的角度来看，这是令人担忧的，因为这也是神经发育的关键时期。尤其令人不安的是，每天新增6000多名首次吸食大麻的人，其中62.2%的人年龄在18岁以下。大麻可能成为一种入门药物，因为它的使用可能使个人容易滥用其他非法药物，这一事实进一步强调了这一担忧。此外，大麻的效力(β-9-四氢大麻酚浓度)在美国现在超过10%(1983年为4%)，这可能会对正常的大脑功能产生不可预见的后果。鉴于大量个人经常吸食大麻，彻底了解与其行为和生理影响相关的神经机制具有相当重要的意义。可以说，小脑中含有大脑中密度最高的CB1受体。虽然众所周知，9-THC会导致认知功能异常，如短期记忆和注意力，但研究外源性大麻对联想学习的影响的数据很少，特别是当它与小脑和前脑依赖的经典眨眼条件反射(EBC)有关时。我们小组早期的工作表明，在人类中，慢性大麻使用改变了小脑依赖延迟EBC的条件反应(CR)的获得和计时，但不影响前脑依赖的跟踪EBC任务。然而，目前尚不清楚长期吸食大麻者中观察到的缺陷是由于9-THC的残留效应、大麻中存在的其他一些大麻素、CB1下调，还是由于寻求毒品的个人发病前的差异所致。因此，目前应用的总体目标是调查急性、静脉注射。9-THC给药分别用Delay和TRACE EBC评估了人类小脑和前脑依赖的联想学习。根据已知的CB1在小脑中的作用，假设的结果是9-THC(与安慰剂相比)将以剂量依赖的方式诱导小脑依赖延迟EBC的损害(CRS百分比减少和CR潜伏期改变)。预计9-THC对前脑依赖的微量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.