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的影响，Delta9-tetrahydrocanbinol（THC）对海马神经生理学的影响。 一系列实验涉及重复的腹腔。在不同的时间内注射THC，然后从药物中退出的时期，然后评估包含啮齿动物海马的大脑切片中的电生理参数。 今年早些时候发表的这些研究的结果表明，在用THC进行7D治疗后，该药物在海马中使用LC-MS在海马中无法检测到。但是，7d暴露于THC会产生对GABA抑制的耐受性，而不是大麻素激动剂Win55,212-2释放的谷氨酸释放。此外，与对照不同，来自慢性THC动物​​的海马切片未显示长期增强（LTP），这是学习和记忆的细胞相关性。单个THC的一次注射不足以阻止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。 这些实验还将定义啮齿动物海马中急性和重复的THC暴露的后果，并将定义CB1受体在整个小鼠寿命中的认知中的重要性。