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，其特征是突触传播的改变，有助于成瘾相关过程的进展，包括奖励，依赖性和复发。尼古丁的动机和成瘾性特性至关重要的是激活中唇胶多巴胺（DA）电路，大多数用于戒烟的治疗方法都集中在该系统上。内源性大麻素相关的脂质（ERL），包括油酰乙醇酰胺（OEA），通过对这些突触对刺激依赖性影响进行调节，并已提出靶向OEA信号传导的药物作为一种用于治疗胰岛成瘾的替代治疗策略。由脂肪酸酰胺水解酶（FAAH）介导的OEA降解途径以及推定的OEA受体过氧化物酶体增殖剂增殖剂 - 活化受体α（PPARALPHA）已被大量追求作为药理靶标，用于治疗烟碱成瘾的药理靶标，但鲜为人知，但已知鲜为人知。 pParalpha的激活诱导胆碱能和谷氨酸能传播的可塑性，在长期尼古丁自我给药后都失调。我们建议，OEA驱动的胆碱能可塑性（在抑郁症的pParalpha影响下）和谷氨酸能塑性（在主动pParalpha信号传导期间）之间会产生负螺旋，从而在促进Nicotine Addictio中起功能起作用。 Nape-PLD在VTA胆碱能和谷氨酸能可塑性中的作用将使用在我的K99训练阶段获得的电生理技术与体内微透析结合使用。然后，在开发了这些技术之后，我们将研究长期尼古丁自我给药后NAPE-PLD的功能和行为作用，该项目的独立R00阶段。这项工作将为导致奖励功能障碍和尼古丁依赖的机制提供重要的见解，并为药物治疗开发提供了另一种途径。