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

描述（由申请人提供）：尼古丁成瘾是一种复杂的行为现象，其特征在于突触传递的改变，这有助于成瘾相关过程的进展，包括奖赏、依赖和复发。尼古丁的动机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个系统上。内源性大麻素相关脂质（ERL），包括油酰乙醇胺（OEA）调节这一电路通过施加刺激依赖性的影响，在这些突触，靶向OEA信号转导的药物已被提出作为一种替代的治疗策略，用于治疗尼古丁成瘾。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）已被大量用作治疗尼古丁成瘾的药理学靶点，但对OEA产生的机制知之甚少。PPARα的激活诱导胆碱能和多巴胺能传递的可塑性，这两种传递在长期尼古丁自我给药后均失调。我们认为，OA驱动的胆碱能可塑性（在抑制的PPARα影响期间）和多巴胺能可塑性（在激活的PPAR α信号传导期间）之间的波动产生了一个负螺旋，在促进尼古丁成瘾中起着功能性作用。NAPE-PLD在腹侧被盖区胆碱能和多巴胺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学技术结合体内微透析进行功能研究。在开发了这些技术后，我们将研究NAPE-PLD在长期尼古丁自我给药后的功能和行为作用，该项目的独立R 00阶段。这项工作将提供重要的洞察机制，导致奖励功能障碍和尼古丁依赖，并提供了另一种途径的药理学发展。

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 (PPARα) has been heavily pursued as pharmacological targets for treating nicotine addiction, yet comparatively little is known about the mechanisms of OEA production. Activation of PPARα 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 PPARα 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.