Consequences of prolonged exposure to delta9-THC on brain function

长期接触 delta9-THC 对脑功能的影响

• 批准号: 7593291
• 负责人: Carl R Lupica
• 金额: $ 44.99万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593291
• 关键词: AIDS Dementia Complex; AM 251; Acute; Adverse effects; Affect; Age; Agonist; Alzheimer' s Disease; Animal Model; Animals; Binding; Brain; CNR1 gene; Cannabinoids; Chronic; Cognition; Cognitive; Cognitive deficits; Disruption; Drug abuse; Evaluation; Exposure to; Genetic; Glutamates; Goals; Hippocampus (Brain); Human; Human body; Illicit Drugs; Individual; Injection of therapeutic agent; Knowledge; Learning; Long-Term Potentiation; Longevity; Marijuana; Memory; Memory impairment; Molecular Target; Mus; Neurobiology; Neurons; Organism; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Population; Process; Publishing; Reaction Time; Rodent; Role; Series; Short-Term Memory; Slice; Tetrahydrocannabinol; Thinking; Time; Urination; Whole-Cell Recordings; Withdrawal; cannabinoid receptor; cognitive function; drug withdrawal; gamma-Aminobutyric Acid; mouse model; neurophysiology; prevent; receptor; research study; synaptic function

This project was initiated to fill a void in our knowledge regarding the neurobiological substrates of the the adverse effects of chronic marijuana use on cognition in humans. It is well-known that both acute and chronic marijuana use in humans impairs short-term memory, reaction times, and general higher-order cognitive processing. These studies seek to utilize animal models to explore the effects of both acute and chronic exposure to the main psychoactive ingredient in marijuana, delta9-tetrahydrocannabinol (THC) on the neurophysiology of the hippocampus. One series of experiments involve repeated i.p. injections with THC for varying periods of time, followed by varying periods of withdrawal from the drug, and then evaluation of electrophysiological parameters in brain slices containing the rodent hippocampus. Results from these studies, published earlier this year, indicate that following a 1d withdrawal from a 7d treatment with THC, the drug was undetectable in hippocampus using LC-MS. However, the 7d exposure to THC produced tolerance to the inhibition of GABA, but not glutamate release by the cannabinoid agonist WIN55,212-2. Additionally, unlike controls, the hippocampal slices from the chronic THC animals did not demonstrate long-term potentiation (LTP), a cellular correlate of learning and memory. A single injection of THC was insufficient to block LTP, the LTP blockade persisted for 3d after the last THC injection, and it was prevented by pretreatment of the animals before each THC injection with the antagonist AM251 (2 mg/kg). Additional experiments now under way will examine the hypothesis that the CB1 cannabinoid receptor is necessary to permit normal cognition and learning and memory over the life span of an organism. For these studies, we are comparing the level of LTP in hippocampal brain slices obtained from CB1+/+ and -/- animals at various ages. In addition, we are defining the actions of acute THC exposure on individual neurons in hippocampal brain slices using whole-cell recordings. The majority of studies to date have utilized synthetic CB agonists to assess the role of CB1 receptors in modulating hippocampal synaptic function. By comparing the effects of THC to those of these synthetic agonists, we hope to identify putative molecular targets of THC that may help explain memory impairments in humans following chronic marijuana use. These experiments will also define the consequences of both acute and repeated THC exposure in the rodent hippocampus and will define the importance of the CB1 receptor in cognition throughout the lifespan of the mouse.

该项目的发起是为了填补我们关于长期吸食大麻对人类认知产生不利影响的神经生物学基础的知识空白。众所周知，人类急性和慢性吸食大麻都会损害短期记忆、反应时间和一般高阶认知处理。这些研究试图利用动物模型来探讨急性和慢性接触大麻中主要精神活性成分 δ9-四氢大麻酚 (THC) 对海马体神经生理学的影响。 一系列实验涉及重复腹腔注射。不同时间段注射 THC，然后不同时间段停药，然后评估包含啮齿动物海马体的脑切片中的电生理参数。 今年早些时候发表的这些研究结果表明，在 7 天的 THC 治疗停药 1 天后，使用 LC-MS 在海马中检测不到该药物。然而，接触 THC 7 天会产生对 GABA 抑制的耐受性，但不会对大麻素激动剂 WIN55,212-2 的谷氨酸释放产生耐受性。此外，与对照组不同，慢性 THC 动物的海马切片没有表现出长时程增强（LTP），这是学习和记忆的细胞相关性。单次注射THC不足以阻断LTP，最后一次THC注射后LTP阻断持续3天，并且通过在每次THC注射前用拮抗剂AM251（2mg/kg）对动物进行预处理来预防LTP阻断。 目前正在进行的其他实验将验证以下假设：CB1 大麻素受体对于生物体整个生命周期内的正常认知、学习和记忆是必需的。在这些研究中，我们比较了从不同年龄的 CB1+/+ 和 -/- 动物获得的海马脑切片中的 LTP 水平。此外，我们正在使用全细胞记录来定义急性 THC 暴露对海马脑切片中单个神经元的作用。 迄今为止，大多数研究都利用合成 CB 激动剂来评估 CB1 受体在调节海马突触功能中的作用。 通过比较 THC 与这些合成激动剂的作用，我们希望确定 THC 的假定分子靶标，这可能有助于解释人类长期吸食大麻后的记忆障碍。 这些实验还将确定啮齿动物海马体中急性和重复 THC 暴露的后果，并将确定 CB1 受体在小鼠整个生命周期认知中的重要性。