The role of the OEA synthase NAPE-PLD in nicotine signaling and reward

OEA 合酶 NAPE-PLD 在尼古丁信号传导和奖励中的作用

基本信息

批准号：
8871705
负责人：
Matthew Wallace Buczynski
金额：
$ 14.18万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2014-07-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8871705
关键词：
2-arachidonylglycerol Abstinence Anabolism Animals Behavior Behavioral Brain Chronic Complex Cues Data Degradation Pathway Dependence Depressed mood Development Dialysis procedure Dopamine Dopaminergic Cell Dose Drug Targeting Electrophysiology (science)Endocannabinoids Enzymes Functional disorder Glutamates Goals Health Intravenous Knockout Mice Lipids Mediating Microdialysis Molecular Motivation Mus N-Methyl-D-Aspartate Receptors NR2A NMDA receptor Nicotine Nicotine Dependence Nicotinic Receptors Nucleus Accumbens PPAR alpha Pathway interactions Pharmaceutical Preparations Phase Phosphorylation Play Presynaptic Terminals Procedures Process Production Property Recording of previous events Rewards Role Saline Self Administration Signal Transduction Slice Stimulus Study models Synapses Synaptic Transmission Synaptic plasticity System Techniques Testing Therapeutic Time Training Up-Regulation Ventral Tegmental Area Work addiction behavioral response cholinergic dependence relapse dopaminergic neuron drug of abuse experience fatty acid amide hydrolase in vivo insight neuronal cell body new therapeutic target nicotine abuse oleoylethanolamide postsynaptic presynaptic receptor receptor expression research study smoking cessation transmission process

项目摘要

DESCRIPTION (provided by applicant): Nicotine addiction is a complex behavioral phenomenon, characterized by alterations in synaptic transmission which contribute to a progression of addiction-related processes including reward, dependence, and relapse. The motivational and addictive properties of nicotine are critically reliant on activation of the mesolimbic dopamine (DA) circuitry, and most therapeutic approaches for smoking cessation have focused on this system. Endocannabinoid-related lipids (ERL) including oleoylethanolamide (OEA) modulate this circuitry by exerting a stimulus-dependent influence at these synapses, and drugs targeting OEA signaling have been proposed as an alternative therapeutic strategy for treating nicotine addiction. Both the OEA degradation pathway, mediated by fatty acid amide hydrolase (FAAH), as well as the presumptive OEA receptor peroxisome proliferator- activated receptor alpha (PPARalpha) has been heavily pursued as pharmacological targets for treating nicotine addiction, yet comparatively little is known about the mechanisms of OEA production. Activation of PPARalpha induces plasticity of cholinergic and glutamatergic transmission, which are both dysregulated following long- term nicotine self-administration. We propose that OEA-driven fluctuations between cholinergic plasticity (during depressed PPARalpha influence) and glutamatergic plasticity (during active PPARalpha signaling) create a negative spiral that plays an functional role in facilitating nicotine addictio. The role of NAPE-PLD in VTA cholinergic and glutamatergic plasticity will be functionally studied using electrophysiology techniques acquired in my K99 training phase in combination with in vivo micro dialysis. Having developed these techniques, we will then study the functional and behavioral role of NAPE-PLD following long-term nicotine self-administration the independent R00 phase of the project. This work will provide important insight into the mechanisms leading to reward dysfunction and nicotine dependence, and provide another avenue for pharmacotherapeutic development.

描述（由申请人提供）：尼古丁成瘾是一种复杂的行为现象，其特征是突触传递的改变，这有助于成瘾相关过程的进展，包括奖赏、依赖和复发。尼古丁的激励和成瘾特性很大程度上依赖于中脑边缘多巴胺（DA）回路的激活，大多数戒烟治疗方法都集中在该系统上。包括油酰乙醇酰胺 (OEA) 在内的内源性大麻素相关脂质 (ERL) 通过对这些突触施加刺激依赖性影响来调节该回路，并且针对 OEA 信号传导的药物已被提议作为治疗尼古丁成瘾的替代治疗策略。由脂肪酸酰胺水解酶 (FAAH) 介导的 OEA 降解途径以及假定的 OEA 受体过氧化物酶体增殖物激活受体 α (PPARα) 已被大力研究作为治疗尼古丁成瘾的药理学靶标，但人们对它知之甚少。 OEA 的产生机制。 PPARα 的激活会诱导胆碱能和谷氨酸能传递的可塑性，而长期自我服用尼古丁后，这两种传递都会失调。我们认为，OEA 驱动的胆碱能可塑性（PPARα 影响期间）和谷氨酸可塑性（PPARα 信号传导活跃期间）之间的波动会产生负螺旋，在促进尼古丁成瘾方面发挥功能性作用。 NAPE-PLD 在 VTA 胆碱能和谷氨酸可塑性中的作用将使用我在 K99 培训阶段获得的电生理学技术结合体内微透析进行功能研究。开发了这些技术后，我们将在项目的独立 R00 阶段长期尼古丁自我给药后研究 NAPE-PLD 的功能和行为作用。这项工作将为导致奖赏功能障碍和尼古丁依赖的机制提供重要的见解，并为药物治疗的发展提供另一条途径。