Molecular target and circuitry underlying the preclinical effects of psychedelics in models of opioid use disorder

阿片类药物使用障碍模型中迷幻药临床前作用的分子靶点和电路

基本信息

批准号：
10751173
负责人：
Alaina Jaster
金额：
$ 4.16万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751173
关键词：
Accidents Acute Adult Affect Alcohol consumption Alcohols Amphetamines Animal Model Animals Association Learning Behavior Behavioral Behavioral Model Biological Assay Brain Cessation of life Clinical Clinical Research Clinical Trials Cognition Complex Critical Thinking Data Disease Dose Drug Interactions Drug Modulation Drug usage Enterobacteria phage P1 Cre recombinase Extinction Female Fright Future Goals Hallucinogens Human Investigation Knockout Mice Life Lysergic Acid Diethylamide Memory Mental Depression Methods Modeling Molecular Molecular Target Motivation Mus Neurobiology Nicotine Nucleus Accumbens Opioid Opioid Receptor Oxycodone Patients Perception Pharmaceutical Preparations Pharmacology Pharmacotherapy Play Pre-Clinical Model Process Psilocybin Psychotropic Drugs Publishing Rattus Receptor Activation Recording of previous events Regulation Relapse Reporting Research Rewards Rodent Model Role Scientist Self Administration Sensory Serotonin Serotonin Receptor 5-HT2A Signal Transduction Stimulant Stimulus Structure Substance Use Disorder Sucrose Surveys Techniques Testing Therapeutic Therapeutic Effect Training Tryptamines United States Viral Vector Wild Type Mouse Writing addiction behavioral phenotyping clinically relevant conditioned place preference conditioning cost craving delivery vehicle drug of abuse frontal lobe hippocampal pyramidal neuron human model interest maladaptive behavior male neural circuit nicotine use novel opioid misuse opioid use disorder overdose death pre-clinical preference prescription opioid abuse serotonin receptor side effect success synthetic opioid targeted treatment

项目摘要

Summary In 2020, 91,799 drug overdose deaths occurred in the United States , over a third of which were related to synthetic opioids. Opioid use disorder (OUD), like other substance use disorders (SUD), is characterized maladaptive behavioral allocation away from other rewarding aspects of life following prolonged use, as well as large rates of relapse. While pharmacotherapies exist for OUD, they tend to only target the opioid receptors rather than the underlying mechanisms behind the maladaptive behaviors. Serotonin (5-hydroxytryptamine; 5-HT) is involved in modulation of cravings and regulation of motivational reward-related behaviors, thought to be due to a top-down processing method of external and internal stimuli. Serotonin 2A receptors (5-HT2AR) are widespread throughout the brain and most densely populate layer V pyramidal neurons in the cortex. These cortical pyramidal neurons project to several subcortical regions, including the nucleus accumbens, which is associated with the neurobiology of addiction. 5- HT2ARs are the main target of classic psychedelics, which produce alterations in processes related to cognition, perception and sensory processing via activation of these receptors. These compounds may possess the ability to alter behaviors associated with reward-related behaviors, such as context-induced relapse, which plays a large part in substance use disorders. Moreover, these compounds are being studied in clinical trials for their ability to treat substance use disorders. The proposed study will investigate whether a psychedelic can alter drug-related behaviors and the role of cortical 5-HT2AR in modulation of these behaviors. This study will focus on tryptamine psychedelic, psilocybin, which has a chemotype very similar to serotonin that activates mainly 5-HT2AR and 5-HT1Rs. Throughout the proposed study, I will be assessing the role of the 5-HT2AR by utilizing cre-recombinase viral vector delivery which will allow me to assess specific loci of 5-HT2AR and how activation of these receptors modulates drug-context related behaviors. The success of this studies will identify important mechanisms behind this The success of this studies will identify important mechanisms behind this. The success of this studies will identify important mechanisms behind this powerful drug class, including circuitry that could be utilized to develop safe, non-addictive and non-hallucinogenic pharmacotherapies to treat OUD. The proposed will facilitate my training in molecular techniques and animal behavioral models as well as give me opportunities to advance my scientific writing, critical thinking and prepare me for a future as an independent research scientist.

概括 2020年，美国发生了91,799例药物过量死亡事件，其中超过三分之一是与合成阿片类药物有关。阿片类药物使用障碍 (OUD)，与其他物质使用障碍一样（SUD），其特征是适应不良的行为分配远离其他奖励方面长期使用后寿命延长，复发率也很高。虽然药物疗法的存在 OUD，它们往往只针对阿片受体而不是潜在机制不良适应行为的背后。血清素（5-羟色胺；5-HT）参与渴望的调节和动机奖励相关行为的调节，被认为是由于外部和内部刺激的自上而下的处理方法。 5-羟色胺2A受体 (5-HT2AR) 广泛分布在整个大脑中，并且在第五层锥体中分布最密集皮层中的神经元。这些皮质锥体神经元投射到几个皮质下区域，包括伏隔核，它与成瘾的神经生物学有关。 5- HT2AR 是经典致幻剂的主要目标，它会产生过程的改变通过激活这些受体与认知、知觉和感觉处理相关。这些化合物可能具有改变与奖励相关行为相关的行为的能力，例如环境诱发的复发，这在物质使用障碍中起着很大的作用。此外，这些化合物正在临床试验中研究其治疗物质的能力使用障碍。拟议的研究将调查迷幻药是否可以改变与药物相关的症状行为以及皮质 5-HT2AR 在调节这些行为中的作用。这项研究将重点关注色胺迷幻药裸盖菇素，其化学型与血清素非常相似主要激活 5-HT2AR 和 5-HT1R。在整个拟议的研究中，我将评估通过利用 cre 重组酶病毒载体传递来发挥 5-HT2AR 的作用，这将使我能够评估 5-HT2AR 的特定位点以及这些受体的激活如何调节药物背景相关行为。这项研究的成功将确定其背后的重要机制这项研究的成功将确定其背后的重要机制。此次活动的成功研究将确定这种强大药物类别背后的重要机制，包括电路可用于开发安全、非成瘾性和非致幻性药物疗法治疗 OUD。该提议将促进我在分子技术和动物技术方面的培训行为模型以及给我机会来提升我的科学写作、批判性思考并为我作为一名独立研究科学家的未来做好准备。