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: 8451356
• 负责人: PATRICK David SKOSNIK
• 金额: $ 15.71万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8451356
• 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; 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; screening; 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.

描述（由申请人提供）：大麻或 Cannabis sativa 是美国最常用的非法药物，在青春期和成年早期使用量增加，从公共卫生角度来看，这是令人担忧的，因为这些也是。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。大麻可能会成为一种入门毒品，因为它的使用可能会使个人滥用其他非法药物。此外，大麻的效力（δ-9-四氢大麻酚（¿9-THC）的浓度）现已超过。在美国，这一比例为 10%（1983 年为 4%），鉴于大量人经常吸食大麻，这可能会对正常大脑功能产生不可预见的后果。深入了解与其行为和生理效应相关的神经机制具有相当大的相关性，而众所周知，小脑可能含有最高密度的 CB1 受体。 9-THC 会导致认知功能异常，例如短期记忆和注意力，但很少有数据检查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，但不会改变前脑依赖性微量 EBC然而，目前尚不清楚长期大麻使用者观察到的缺陷是否是由于 ¿ 9- THC、大麻中存在的一些其他大麻素、CB1 下调或寻求药物的个体的病前差异因此，本申请的总体目标是调查急性、静脉注射是否会导致药物滥用。 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，分别通过延迟和跟踪 EBC 进行评估，基于小脑中已知的 CB1 作用，捕获的结果是 ¿ 9-THC（与安慰剂相比）将以剂量依赖性方式引起小脑依赖性延迟 EBC 损害（CR 百分比降低和 CR 潜伏期改变）。 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，这将有助于阐明其机制。最常用的滥用药物之一的作用。

项目成果

The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (Δ9-THC) in humans.

静脉注射 δ-9-四氢大麻酚 (α9-THC) 对人体的剂量依赖性精神运动作用。

• 发表时间: 2018
• 作者: Boggs, Douglas L;Cortes;Surti, Toral;Luddy, Christina;Ranganathan, Mohini;Cahill, John D;Sewell, Andrew R;D'Souza, Deepak C;Skosnik, Patrick D
• 通讯作者: Skosnik, Patrick D