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: 7966845
• 负责人: Carl R. Lupica
• 金额: $ 47.16万
• 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/7966845
• 关键词: AIDS Dementia Complex; AM 251; Acute; Adenosine; Adenosine A1 Receptor; Adverse effects; Affect; Age; Agonist; Alzheimer' s Disease; Animal Model; Animals; Area; Behavior; Binding; Brain; CNR1 gene; Cannabinoids; Chronic; Cognition; Cognitive; Cognitive deficits; 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; Longevity; Marijuana; Marijuana Smoking; Measures; Memory; Memory impairment; Mental disorders; Molecular Target; Neurobiology; Neurons; Organism; Physiological; Population; Presynaptic Terminals; Process; Property; Publishing; Reaction Time; Regulation; Reporting; Role; Schizophrenia; Short-Term Memory; Signal Transduction; Site; Slice; Structure; Synaptic Transmission; System; Tetrahydrocannabinol; Ventral Tegmental Area; Whole-Cell Recordings; Work; cannabinoid receptor; cognitive function; depression; dopaminergic neuron; gamma-Aminobutyric Acid; molecular site; 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 tegmanetal 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). 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. 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 that is in review, 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.

该项目的开始是为了填补有关慢性大麻使用对人类认知的不良影响的神经生物学底物的知识。众所周知，急性和慢性大麻在人类中的使用都损害了短期记忆，反应时间和一般的高阶认知处理。这些研究旨在利用动物模型来探索大麻中急性和慢性暴露于主要的精神活性成分，Delta9-tetrahydrocanbinol（THC）对海马神经生理学以及现在的腹侧Tegmanetal区域（VTA）（VTA）的影响。 我们先前发表的研究表明，重复注射THC的长期增强（LTP）是学习和记忆的细胞相关性。此外，单个THC的单个注射不足以阻止LTP，LTP阻滞在上次THC注射后持续了3D，并且通过对拮抗剂AM251（2 mg/kg）注射每次THC之前对动物进行预处理的预处理。 现在正在进行的其他实验将研究以下假设：CB1大麻素受体对于允许在生物体的寿命中允许正常的认知，学习和记忆。对于这些研究，我们比较了从不同年龄段的CB1+/+和 - / - 动物获得的海马脑切片中LTP的水平。此外，我们使用全细胞记录来定义急性THC暴露对海马大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。 通过将THC与这些合成激动剂的影响进行比较，我们希望确定THC的推定分子靶标，可以帮助解释长期使用大麻后人类的记忆障碍。 我们最近的工作发现，虽然THC在海马抑制谷氨酸释放中是部分激动剂，但当对海马抑制GABA释放的效果测量时，它是一种完整的激动剂。 我们认为，这种差异是由于该大脑结构中的GABA能轴突末端与谷氨酸末端的CB1受体密度更高，并且我们提出，这提供了有力的证据表明，THC相互作用的主要位点破坏了海马依赖性依赖性的记忆是在Gabaegric Systems上。 在正在综述的另一项研究中，我们报道说，当腺苷A1受体被阻断时，大麻素对海马谷氨酸释放的影响可以大大增强。 这表明内源性腺苷参与调节海马中CB1受体信号的强度，并且内源性大麻素的功能受到腺苷系统的控制。