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

• 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
• 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

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(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，这有助于一系列与成瘾相关的过程，包括奖赏、依赖和复发。尼古丁的兴奋和成瘾特性严重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这一系统上。包括油酰乙醇胺(OEA)在内的内源性大麻素相关脂(ERL)通过在这些突触上施加刺激依赖的影响来调节这一回路，针对OEA信号的药物已被建议作为治疗尼古丁成瘾的替代治疗策略。作为治疗尼古丁成瘾的药理靶点，脂肪酸酰胺水解酶(FAAH)介导的OEA降解途径以及推测的OEA受体PPARpha都是尼古丁成瘾的治疗靶点，但对OEA产生的机制知之甚少。PPARα的激活诱导了胆碱能和谷氨酸能传递的可塑性，在长期服用尼古丁后，这两种传递都是失调的。我们认为，OEA驱动的胆碱能可塑性(在抑制PPARpha影响期间)和谷氨酸可塑性(在活跃的PPARpha信号转导期间)之间的波动产生了一个负螺旋，在促进尼古丁成瘾方面发挥了功能作用。NAPE-PLD在VTA胆碱能和谷氨酸能可塑性中的作用将利用我在K99训练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，我们将研究长期尼古丁自我给药后NAPE-PLD的功能和行为作用，这是该项目的独立R00阶段。这项工作将对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。