CB1 Mediation of Cerebellum Versus Forebrain-Dependent Associative Learning

小脑与前脑依赖的联想学习的 CB1 调节

• 批准号: 8299799
• 负责人: PATRICK David SKOSNIK
• 金额: $ 19.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299799
• 关键词: Acute; Adolescence; Adolescent; Affect; Age; Agonist; Air; Animal Model; Animals; Ataxia; Attention; Behavioral; Blinking; Brain; Brain Stem; CNR1 gene; Cannabinoids; Cannabis; Cannabis Abuse; Cannabis sativa plant; Caring; Cell Communication; Cell Nucleus; Cerebellar cortex structure; Cerebellum; Chronic; Conditioned Stimulus; Cornea; Data; Dependence; Development; Dose; Double-Blind Method; Down-Regulation; Endocannabinoids; Evaluation; Exhibits; Eye; Fright; Future; General Population; Glutamates; Human; Illicit Drugs; Impairment; Individual; Intravenous; Knockout Mice; Laboratories; Learning; Left; Marijuana; Measures; Mediating; Mediation; Mississippi; Monitor; Motor; Neurobiology; Outcome; Participant; Pharmaceutical Preparations; Physiological; Placebo Control; Placebos; Prevention; Prosencephalon; Public Health; Purkinje Cells; Randomized; Receptor Activation; Residual state; Response Latencies; Role; Screening procedure; Short-Term Memory; Stimulus; Structure; Synaptic plasticity; System; Testing; Tetrahydrocannabinol; Time; Translational Research; United States; United States Substance Abuse and Mental Health Services Administration; Universities; Work; base; classical conditioning; cognitive function; conditioning; critical period; density; drug of abuse; endogenous cannabinoid system; experience; granule cell; improved; information processing; neural circuit; neurodevelopment; neuromechanism; presynaptic; public health relevance; receptor downregulation; receptor function; relating to nervous system; research study; response; young adult

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).

描述（由申请人提供）：大麻或 Cannabis sativa 是美国最常用的非法药物。使用水平的增加发生在青春期和成年早期，从公共卫生的角度来看，这是令人担忧的，因为这些也是神经发育的关键时期。尤其令人不安的是，每天新增吸食大麻的人数超过6000人，其中62.2%年龄在18岁以下。大麻可能充当入门毒品，因为使用大麻可能会使个人滥用其他非法药物，这一事实进一步加剧了这种担忧。此外，在美国，大麻的效力（δ9-四氢大麻酚 (¿9-THC) 的浓度）现已超过 10%（1983 年为 4%），这可能会对正常大脑功能产生不可预见的后果。鉴于大量定期吸食大麻的人，彻底了解与其行为和生理影响相关的神经机制具有相当大的意义。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，但很少有数据检验外源性大麻素对联想学习的影响，特别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，长期使用大麻会改变小脑依赖性延迟 EBC 中的条件反应 (CR) 获得和时间安排，但不会改变前脑依赖性微量 EBC 任务。然而，目前尚不清楚在长期大麻使用者中观察到的缺陷是否是由于 9-THC、大麻中存在的其他一些大麻素的残留影响、CB1 下调或吸毒个体的病前差异所致。因此，当前申请的总体目标是研究是否急性、静脉注射。分别用延迟和微量 EBC 进行评估，9- THC 给药介导人类小脑依赖性联想学习与前脑依赖性联想学习。基于已知的 CB1 在小脑中的作用，假设结果是 9-THC（与安慰剂相比）将以剂量依赖性方式诱导小脑依赖性延迟 EBC 损伤（CR 百分比降低和 CR 潜伏期改变）。还预计 9-THC 对前脑依赖性微量 EBC 影响很小或没有影响。总而言之，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。 公共健康相关性：本申请的公共健康相关性可概括如下：1）大麻暴露可能会导致内源性大麻素系统的神经变化，而这种变化对大脑内信息处理的影响尚不清楚。 2) 了解大麻中的活性成分 (Delta-9-THC) 如何与信息处理背后的神经基质相互作用将改善对大麻滥用/依赖的护理和预防。 3）拟议的研究对于未来的转化研究具有很高的潜力，因为眨眼条件反射任务广泛应用于动物研究中，并且介导该任务的神经回路在不同物种之间得到了很好的保守（即当前研究的结果将在未来的大麻素功能动物模型中进行测试）。