Characterization of the Role of mTOR Signaling in Opiate Action

mTOR 信号传导在阿片类药物作用中的作用表征

基本信息

批准号：
7545148
负责人：
Michelle Suzanne Mazei-Robison
金额：
$ 5.13万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7545148
关键词：
Acetaminophen Adolescent Adult Affect Behavior Behavior Therapy Behavioral Biochemical Brain Brain region Brain-Derived Neurotrophic Factor Cell Size Chronic Cocaine Development Dominant-Negative Mutation Dopaminergic Cell Dose Down-Regulation Drug Prescriptions Drug abuse Drug usage Goals Heroin Homologous Gene Human Hydrocodone Infusion procedures Laboratories Laboratory Finding Lead Mediating Medical Molecular Morphine Neurobiology Neurons Numbers Opiates Oxycodone Pain Pain Disorder Pathway interactions Patients Pharmaceutical Preparations Population Protein Overexpression Rattus Rewards Role Self Administration Signal Pathway Signal Transduction Sirolimus Teenagers Therapeutic Uses Ventral Tegmental Area Vicodin Viral Western Blotting Work addiction chronic pain concept drug of abuse drug reward human IRS2 protein inhibitor/antagonist neuroadaptation prescription document prescription drug abuse prescription procedure response size

项目摘要

DESCRIPTION (provided by applicant): Both the medical and nonmedical use of opiate drugs have greatly increased in the U.S. in recent years. This increase is especially noteworthy in the increased number of teenagers abusing prescription opiate drugs. Despite this increase, very little is known about the neuroadaptations that occur with chronic opiate use. The goal of this project is to identify the underlying molecular signals that contribute to neuroadaptation to chronic opiate use, specifically the mechanisms that cause a decrease in the size of dopaminergic ventral tegmental (VTA) neurons and the corresponding behavioral adaptation of reward tolerance. Previous work in the Nestler laboratory has established a chronic morphine paradigm that decreases the size of dopaminergic cells in the VTA in a BDNF- and PI3K/Akt-dependent manner. Further, changes in PI3K/Akt signaling in the VTA were found to be necessary and sufficient to produce reward tolerance. This project aims to determine what signaling pathways downstream of Akt modulate this change in cell size and behavior. One prominent signaling pathway that is known to affect cell size in the CNS as well as in the periphery is the mammalian target of rapamycin (mTOR) pathway. We hypothesize that alterations in mTOR signaling contribute to morphological and behavioral changes produced by chronic morphine. To determine whether mTOR signaling is altered in response to chronic morphine, rats will be treated with morphine and the VTA will be dissected for analysis of biochemical changes by western blot. Additionally, the mTOR inhibitor, rapamycin, will be used to inhibit mTOR signaling in order to determine whether decreased mTOR signaling can block morphine-induced reward tolerance. Finally, local viral-mediated overexpression of wildtype and activating and dominant-negative forms of a key modulator of mTOR signaling, ras homolog enriched in brain (Rheb) will be used to mimic changes induced by chronic opiates and to block chronic opiate effects. Given that the most highly prescribed drug in the U.S. in 2005 was an opiate, hydrocodone with acetaminophen, and that the non-prescription use has also increased, especially in adolescents where use of the opiates Oxycontin and Vicodin is greater than more studied drugs of abuse such as cocaine, investigating the action of opiate drugs on neurobiology and behavior is an important and topical drug abuse project. The goal of our work is to understand the neuroadaptations that occur with chronic opiate use, which may help us to better understand both the addiction liability as well as the phenomenon of reward tolerance, decreased reward for drug leading to escalation of dose.

描述（由申请人提供）：近年来，阿片类药物的医疗和非医疗用途在美国都大大增加。这种增加在滥用处方阿片类药物的青少年数量增加的情况下尤其值得注意。尽管这种增加，但人们对长期使用阿片类药物所产生的神经适应知之甚少。该项目的目标是确定有助于长期使用阿片类药物的神经适应的潜在分子信号，特别是导致多巴胺能腹侧被盖（VTA）神经元尺寸减小的机制以及相应的奖赏耐受行为适应。 Nestler 实验室之前的工作已经建立了一种慢性吗啡范例，该范例以 BDNF 和 PI3K/Akt 依赖性方式减小 VTA 中多巴胺能细胞的大小。此外，VTA 中 PI3K/Akt 信号传导的变化被发现对于产生奖赏耐受是必要且充分的。该项目旨在确定 Akt 下游的哪些信号通路调节细胞大小和行为的这种变化。已知影响中枢神经系统和外周细胞大小的一种重要信号传导途径是哺乳动物雷帕霉素靶点 (mTOR) 途径。我们假设 mTOR 信号传导的改变导致慢性吗啡产生的形态和行为变化。为了确定 mTOR 信号传导是否因慢性吗啡而改变，将用吗啡治疗大鼠，并解剖 VTA 以通过蛋白质印迹分析生化变化。此外，mTOR 抑制剂雷帕霉素将用于抑制 mTOR 信号传导，以确定减少的 mTOR 信号传导是否可以阻断吗啡诱导的奖赏耐受。最后，局部病毒介导的野生型过度表达以及 mTOR 信号传导关键调节剂（大脑中富集的 ras 同源物（Rheb）的激活和显性失活形式）将用于模拟慢性阿片类药物引起的变化并阻止慢性阿片类药物的作用。鉴于 2005 年美国使用最多的处方药物是阿片类药物、氢可酮和对乙酰氨基酚，而且非处方药物的使用也有所增加，特别是在青少年中，阿片类药物奥施康定和维柯丁的使用量高于更多研究的滥用药物例如可卡因，研究阿片类药物对神经生物学和行为的作用是一个重要的、热门的药物滥用项目。我们工作的目标是了解长期使用阿片类药物时发生的神经适应，这可能有助于我们更好地了解成瘾倾向以及奖励耐受现象，即药物奖励减少导致剂量增加。