Molecular sites of delta-9-THC actions on brain function

delta-9-THC 对脑功能作用的分子位点

• 批准号: 8736739
• 负责人: Carl R. Lupica
• 金额: $ 41.39万
• 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/8736739
• 关键词: AIDS Dementia Complex; AM 251; Acute; Adenosine; Adenosine A1 Receptor; Adolescent; Adverse effects; Affect; Agonist; Alzheimer' s Disease; Animal Model; Animals; Area; Axon; Behavior; Beverages; Binding; Birth; Brain; CNR1 gene; Caffeine; Cannabinoids; Cellular Stress; Chronic; Cognition; Cognitive; Cognitive deficits; Data; Drug abuse; Endocannabinoids; Exposure to; Functional disorder; Genetic; Glutamates; Goals; Hippocampus (Brain); Human; Human body; Illicit Drugs; Individual; Injection of therapeutic agent; Knowledge; Learning; Long-Term Potentiation; Marijuana; Marijuana Smoking; Measures; Memory; Memory impairment; Mental Depression; Mental disorders; Metabolic; Metabolic stress; Molecular Target; Moods; Neurobiology; Neuromodulator; Neurons; Physiological; Play; Population; Presynaptic Terminals; Process; Property; Public Health; Publishing; Reaction Time; Receptor Signaling; Regulation; Reporting; Role; Schizophrenia; Seizures; Short-Term Memory; Signal Transduction; Site; Slice; Source; Structure; Synaptic Transmission; System; Tetrahydrocannabinol; Ventral Tegmental Area; Whole-Cell Recordings; Work; cannabinoid receptor; cognitive function; dopaminergic neuron; gamma-Aminobutyric Acid; in utero; molecular site; mossy fiber; mouse model; neurophysiology; prevent; receptor; receptor density; research study; reward circuitry; 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 and now the ventral tegmental area (VTA). Our prior published study showed that repeated injections of THC blocked long-term potentiation (LTP), a cellular correlate of learning and memory. Furthermore, 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). We are also 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. Our most recent work has found that whereas THC acts as a partial agonist in the inhibition of glutamate release in the hippocampus, it is a full agonist when its effects are measured on the inhibition of GABA release in the hippocampus. We believe that this difference is due to a much higher CB1 receptor density on GABAergic axon terminals versus glutamate terminals in this brain structure, and we have proposed that this provides strong evidence that the primary site of THC's interaction to disrupt hippocampal-dependent memory is on GABAergic systems. In a separate study, we have reported that the effects of cannabinoids on hippocampal glutamate release can be greatly potentiated when adenosine A1 receptors are blocked. This suggests that endogenous adenosine is involved in regulating the strength of signaling through CB1 receptors in the hippocampus, and that endocannabinoid function is under control of the adenosine system. This is important because it is well known that the neuromodulator, adenosine, is released during periods of cellular and metabolic stress, and that it plays an important role in terminating seizures. Therefore, we predict that the conditions that regulate adenosine release will also modify the effects of endogenous cannabinoids, and the effects of marijuana in the hippocampus. Current experiments are involved in defining the source and site of action of endogenous adenosine in the hippocampus, with the ultimate goal of identifying how adenosine A1 receptors and endogenous adenosine interfere with cannabinoid receptor signaling. Preliminary data indicate that endogenous adenosine are released from mossy fibers in in area CA3 and this is inhibiting impulse activity in CA3 neuron axons that express cannabinoid CB1 receptors in area CA1. Through this mechanism we hypothesize that endogenous adenosine released during states of high metabolic demand can regulate the functions of endogenous cannabinoids and THC in area CA1 of the hippocampus. Ultimately, this will affect cognition, mood and learning by disrupting hippocampal function. An additional pertinent observation from these studies is that the commonly consumed substance, caffeine, which is available in many forms, can increase the ability of marijuana to disrupt hippocampal function. This could have important implications for the developing brain, either in utero, before birth, or in the adolescent brain. Relevant public health concerns may therefore involve the use of marijuana and beverages containing high levels of caffeine in adolescents, and the adverse cognitive and neurodevelopmental consequences.

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 delta9-四氢大麻酚 (THC) 对海马体和腹侧被盖区 (VTA) 神经生理学的影响。 我们之前发表的研究表明，重复注射 THC 会阻断长时程增强 (LTP)，这是学习和记忆的细胞相关性。此外，单次注射THC不足以阻断LTP，LTP阻断在最后一次THC注射后持续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。 我们还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。 我们最近的工作发现，虽然 THC 在抑制海马谷氨酸释放方面起到部分激动剂的作用，但当测量其对海马 GABA 释放的抑制作用时，它是一种完全激动剂。 我们认为，这种差异是由于该大脑结构中 GABA 能轴突末端的 CB1 受体密度比谷氨酸末端高得多，并且我们提出，这提供了强有力的证据，证明 THC 相互作用破坏海马依赖性记忆的主要部位是在GABA能系统。 在另一项研究中，我们报告称，当腺苷 A1 受体被阻断时，大麻素对海马谷氨酸释放的影响会大大增强。 这表明内源性腺苷参与通过海马 CB1 受体调节信号强度，并且内源性大麻素功能受到腺苷系统的控制。 这很重要，因为众所周知，神经调节剂腺苷是在细胞和代谢应激期间释放的，并且它在终止癫痫发作中发挥着重要作用。 因此，我们预测调节腺苷释放的条件也将改变内源性大麻素的作用以及大麻在海马中的作用。 目前的实验涉及确定海马内源性腺苷的来源和作用位点，最终目标是确定腺苷 A1 受体和内源性腺苷如何干扰大麻素受体信号传导。 初步数据表明，内源性腺苷从 CA3 区的苔藓纤维中释放出来，这抑制了 CA1 区表达大麻素 CB1 受体的 CA3 神经元轴突的冲动活动。 通过这种机制，我们假设在高代谢需求状态下释放的内源性腺苷可以调节海马 CA1 区内源性大麻素和 THC 的功能。 最终，这将通过破坏海马体功能来影响认知、情绪和学习。 这些研究的另一个相关观察结果是，常见消耗的物质咖啡因有多种形式，可以增加大麻破坏海马功能的能力。 这可能对子宫内、出生前或青少年大脑的发育产生重要影响。因此，相关的公共卫生问题可能涉及青少年使用大麻和含有高浓度咖啡因的饮料，以及对认知和神经发育的不良后果。