Mechanistic studies of phosphodiesterase inhibitors in cocaine addiction

磷酸二酯酶抑制剂治疗可卡因成瘾的机制研究

基本信息

批准号：
9012061
负责人：
Qing-song Liu
金额：
$ 32.19万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9012061
关键词：
5&apos -AMP-activated protein kinase AMPA Receptors Addictive Behavior Adenylate Cyclase Affect Agonist Animals Attenuated Behavior Behavioral Biological Assay CNR1 gene Cells Chemosensitization Clinical Trials Cocaine Cocaine Dependence Cyclic AMP Cyclic AMP-Dependent Protein Kinases Development Dopamine Drug Addiction Drug abuse Effectiveness Endocannabinoids Endocytosis FDA approved FRAP1 gene Funding Goals Health Health Benefit Inhibitory Synapse Injection of therapeutic agent Knock-out Knowledge Left Long-Term Depression Lung diseases Mediating Memory Microinjections Modeling Modification Molecular Target Mus Neurons PI3 gene Pathway interactions Personal Satisfaction Pharmaceutical Preparations Pharmacotherapy Phosphodiesterase Inhibitors Protein Biosynthesis Protein-Serine-Threonine Kinases Proteins Public Health Regulation Repression Research Resveratrol Rewards Role Rolipram Self Administration Signal Pathway Signal Transduction Sirolimus Site Specificity Synapses Synaptic plasticity Technology Testing Therapeutic Translations Ventilatory Depression Ventral Tegmental Area addiction age related anti aging attenuation base behavioral sensitization cell type designer receptors exclusively activated by designer drugs dopaminergic neuron drug of abuse endocannabinoid signaling genetic manipulation improved inhibitor/antagonist knock-down metabolic phenotype neural circuit phosphodiesterase IV phosphoric diester hydrolase polyphenol preference receptor coupling recombinase-mediated cassette exchange red wine small hairpin RNA treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Cocaine addiction is a serious public health problem. There are no FDA approved medications for the treatment of cocaine addiction. Previous studies have shown that phosphodiesterase-4 (PDE-4) inhibitor rolipram reduces addictive behavior by multiple drugs of abuse in multiple behavior assays and the ventral tegmental area (VTA) is a primary site that mediates its action. Considering that PDE4 and non-selective PDE inhibitors ameliorate aging-related metabolic phenotypes in animal studies and show effectiveness in treating respiratory diseases and depression in clinical trials, these inhibitors are a promising candidate for developing anti-addiction medications with potential health benefits. The goal of this project is to investigate neural circuits and downstream signaling mechanisms that mediate PDE inhibitor-induced attenuation of cocaine conditioned place preference (CPP) and locomotor sensitization. The central hypothesis is that the PDE inhibitors reduce the behavioral effects of cocaine through activation of exchange proteins activated by cAMP (Epac) and inhibition of the mammalian target of rapamycin (mTOR) signaling in the VTA. The hypothesis will be tested through three Specific Aims: 1) Test if the PDE inhibitors activate Epac signaling in VTA dopamine neurons to attenuate cocaine-induced CPP and locomotor sensitization. Under this Aim, we will use the designer receptors exclusively activated by designer drugs (DREADD) technology to interrogate the neuronal cell-type that mediates the action of PDE inhibitors. We will examine whether disruption of Epac signaling in the VTA abrogates the behavioral effects of the PDE inhibitors. 2) Investigate synaptic mechanisms by which the PDE inhibitors attenuate cocaine CPP. Under this Aim, we will test the hypothesis that the PDE inhibitors induce long-term depression-like synaptic modification, which "neutralizes" cocaine-evoked synaptic potentiation and provides a potential mechanism for the reduction in cocaine CPP induced by PDE inhibitors. 3) Test whether PDE inhibitors reduce cocaine CPP and locomotor sensitization through inhibition of mTOR signaling. Under this Aim, we will use a cre-loxP system to produce conditional knockout of mTOR in the VTA and examine its impact on cocaine-induced CPP and behavioral sensitization and behavioral changes induced by the PDE inhibitors. The identification of downstream targets and molecular mechanisms that mediate the action of the PDE inhibitors is a critical first step toward "repurposing" PDE inhibitors for anti-addiction medications.

描述（由申请人提供）：可卡因成瘾是一个严重的公共卫生问题。没有FDA批准的可卡因成瘾药物。先前的研究表明，磷酸二酯酶4（PDE-4）抑制剂ROLIPRAM在多种行为分析中通过多种滥用药物和腹侧段区域（VTA）降低了成瘾行为，是介导其作用的主要部位。考虑到PDE4和非选择性PDE抑制剂在动物研究中可以改善与衰老相关的代谢表型，并在临床试验中显示出有效治疗呼吸疾病和抑郁症的有效性，因此这些抑制剂是开发具有潜在健康益处的抗吸毒药物的有希望的候选人。该项目的目的是研究介导PDE抑制剂引起的可卡因调节位置偏好（CPP）和运动敏感性的抑制剂衰减的神经回路和下游信号传导机制。中心假设是，PDE抑制剂通过激活cAMP激活（EPAC）激活的交换蛋白（EPAC）和抑制VTA中哺乳动物靶靶标而降低了可卡因的行为影响。该假设将通过三个特定目的进行检验：1）测试PDE抑制剂是否激活VTA多巴胺神经元中的EPAC信号传导，以减轻可卡因诱导的CPP和运动敏化。在此目标下，我们将使用设计器药物（Dreadd）技术专门激活的设计器受体来询问介导PDE抑制剂作用的神经元细胞类型。我们将检查VTA中EPAC信号的破坏是否消除了PDE抑制剂的行为效应。 2）研究PDE抑制剂减轻可卡因CPP的突触机制。在此目标下，我们将检验以下假设：PDE抑制剂会诱导长期抑郁症状突触改性，该抑制剂“中和”可卡因诱发的突触增强，并为PDE抑制剂诱导的可卡因CPP降低提供了潜在的机制。 3）测试PDE抑制剂是否通过抑制MTOR信号传导来减少可卡因CPP和运动敏化。在此目标下，我们将使用CRE-LoxP系统在VTA中产生有条件的MTOR敲除，并检查其对可卡因诱导的CPP以及PDE抑制剂引起的行为敏感性以及行为变化的影响。介导PDE抑制剂作用的下游靶标和分子机制的鉴定是朝着“重新利用” PDE PDE抑制剂的关键第一步。