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

• 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
• 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

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，其中三分之一是 与合成阿片类药物有关。像其他物质使用障碍一样，阿片类药物使用障碍（OUD） （SUD）的特征是适应不良的行为分配，而不是其他有意义的方面 长时间使用后的生活以及大量复发率。而存在药物治疗 Oud，它们倾向于仅靶向阿片受体而不是基本机制 不良适应行为的背后。 5-羟色胺（5-羟基丙胺胺； 5-HT）参与 渴望的调节和激励奖励相关的行为的调节，被认为是 由于自上而下的外部和内部刺激方法。 5-羟色胺2A受体 （5-HT2AR）在整个大脑和最密集的层层V锥体 皮质中的神经元。这些皮质锥体神经元向多个皮层下区域项目， 包括伏隔核，与成瘾的神经生物学有关。 5- HT2AR是经典迷幻药的主要目标，它在过程中产生变化 通过激活这些受体的认知，感知和感觉处理有关。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， 例如上下文引起的复发，在物质使用障碍中起着很大作用。 此外，这些化合物的治疗能力正在临床试验中研究 使用疾病。拟议的研究将调查迷幻药是否可以改变与药物有关的 行为和皮质5-HT2AR在调节这些行为中的作用。这项研究会 专注于色素迷幻的psilocybin，其化学型与5-羟色胺非常相似 这主要激活5-HT2AR和5-HT1R。在整个拟议的研究中，我将评估 5-HT2AR的作用通过利用Cre-Recombinase病毒载体传递，这将使我能够 评估5-HT2AR的特定基因座以及这些受体的激活如何调节药物封闭式 相关行为。这项研究的成功将确定背后的重要机制 这项研究的成功将确定背后的重要机制。这个成功 研究将确定此功能强大的药物类别背后的重要机制，包括电路 可以用来开发安全，非添加性和非凝血素化药物治疗 治疗oud。提出的将促进我在分子技术和动物方面的训练 行为模型，并为我提供了推进我的科学写作，关键的机会 思考并为我做好准备，以成为一名独立研究科学家的未来。