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Novel Molecular Mechanisms of Abusable Drugs

滥用药物的新分子机制

基本信息

批准号：
10171824
负责人：
SOLOMON H. SNYDER
金额：
$ 37.67万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171824
关键词：
Address Affinity Antibodies Antidepressive Agents Area Autophagocytosis Behavioral Binding Binding Proteins Biological Assay Brain Carrier Proteins Cocaine Complex Data Disease Dopamine Dose Drug abuse FRAP1 gene Generations Glyceraldehyde 3-Phosphate Impairment In Vitro Ketamine Knock-in Mouse Knock-out Knockout Mice Laboratories Lead Link Mediating Molecular Monomeric GTP-Binding Proteins N-Methyl-D-Aspartate Receptors N-Methylaspartate National Institute of Drug Abuse Neurons Neurotransmitters Nitric Oxide Nitric Oxide Synthase Type I Opioid Receptor Oxidoreductase Pathway interactions Pharmaceutical Preparations Physiological Process Proteins Psychotropic Drugs Reporting Research Role Signal Pathway Signal Transduction Stimulus Substance abuse problem Synaptic Membranes System Technology Testing Time Work cocaine receptor conditional knockout dopamine transporter drug action drug of abuse in vivo inhibitor/antagonist interest monoamine mouse model nanomolar neurotoxic new therapeutic target novel prevent psychostimulant receptor ubiquitin-protein ligase

项目摘要

Project Summary – Snyder Project Our laboratory has long focused on molecular signaling systems in the brain that underlie actions of psychotropic drugs, especially abusable agents. The present proposal addresses two areas of current interest. Cocaine has long been known to impair monoamine transport with modest potency. We recently discovered a very high affinity cocaine `receptor.' As little as 0.1 nM cocaine induces autophagy in cortical cultures, thousands of times more potent than other actions of the drug. We identified BASP-1 protein as the apparent cocaine target. We propose studies to elucidate cocaine-BASP-1 links and their relevance to psychoactivity of cocaine. In a second project, we will explore how ketamine elicits its antidepressant actions via mTOR. We recently established a relevant pathway wherein NMDA signaling triggers NO generation to nitrosylate glyceraldehyde phosphate dehydrogenase (GAPDH) in a complex with the ubiquitin E3-ligase Siah1. In this complex, Siah1 degrades the small G protein Rheb, a physiologic stimulus for mTOR, thereby leading to diminished mTOR activity. By blocking NMDA receptors, ketamine elicits the reverse process, mTOR enhancement. Utilizing a variety of agents, we propose to explicate this signaling system in an effort to understand psychotomimetic/antidepressant actions of ketamine and, hopefully, lead to more effective/safer therapies.

项目概要-斯奈德项目我们的实验室长期以来一直专注于大脑中的分子信号系统，这些系统是大脑活动的基础。精神药物，特别是可滥用的药物。本提案涉及目前关注的两个领域。长期以来，人们都知道可可碱以适度的效力损害单胺转运。我们最近发现了一个高亲和力可卡因受体。“在皮质培养物中，只要0.1 nM可卡因就能诱导自噬，比药物的其他作用强数千倍。我们确定BASP-1蛋白是可卡因目标我们建议进行研究，以阐明可卡因-BASP-1的联系及其与精神活动的相关性，可卡因在第二个项目中，我们将探索氯胺酮如何通过mTOR发挥其抗抑郁作用。我们最近建立了一个相关的途径，其中NMDA信号触发NO生成亚硝基甘油醛磷酸脱氢酶（GAPDH）与泛素E3-连接酶Siah 1形成复合物。在这个复合体中，Siah 1 降解小G蛋白Rheb，一种mTOR的生理刺激物，从而导致mTOR减少活动氯胺酮通过阻断NMDA受体，可逆转mTOR的增强。利用各种代理，我们建议解释这个信号系统，努力理解氯胺酮的拟精神病/抗抑郁作用，并有望导致更有效/更安全的治疗。