Interactions Between CB1 Receptor and DA Receptors in the Nucleus Accumbens Core

伏核核心 CB1 受体和 DA 受体之间的相互作用

• 批准号: 8139035
• 负责人: Taban none Seif
• 金额: $ 5.3万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139035
• 关键词: 2-arachidonylglycerol; AM 251; Adult; Adverse effects; Agonist; Alcohol consumption; Alcohols; Alzheimer' s Disease; Asthma; Behavior; Behavioral; Biological; Brain; CNR1 gene; Cannabinoids; Cannabis; Cells; Cues; DRD2 gene; Data; Disease; Dopamine; Dopamine D1 Receptor; Dopamine D2 Receptor; Dopamine Receptor; Drug Exposure; Drug abuse; Electrophysiology (science); Endocannabinoids; Enzymes; Ethanol; Exposure to; GTP-Binding Proteins; Glaucoma; Goals; Heroin; Human; Hydrolysis; Immune system; In Vitro; Link; Literature; Malignant Neoplasms; Mediating; Mediator of activation protein; Mentors; Molecular; Nausea; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurons; Nucleus Accumbens; Odors; Pain; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Phospholipase C; Physiological Processes; Play; Preparation; Process; Production; Publications; Quinpirole; Rattus; Reagent; Receptor Activation; Relapse; Reproduction; Research; Rewards; Role; SR 141716A; Self Administration; Signal Transduction; Slice; Source; System; Techniques; Testing; Training; addiction; alcohol relapse; anandamide; craving; design; dopamine system; drug of abuse; endogenous cannabinoid system; in vivo; inhibitor/antagonist; interest; male; member; motivated behavior; nervous system disorder; neuromechanism; novel; novel therapeutic intervention; patch clamp; prevent; problem drinker; public health relevance; receptor; research study; response; rimonabant

DESCRIPTION (provided by applicant): A vast literature has shown that dopamine (DA) signaling in the nucleus accumbens (NAc) is a critical mediator of addiction-related and goal-directed behaviors. Thus, there is considerable interest in understanding the molecular mechanisms through which DA can alter the NAc firing activity and modulate behavior. Previous studies from the Bonci lab found that cooperative activation of DA D1 and D2 receptors increases firing of NAc neurons. Interestingly, many motivated and addiction-related behaviors are sustained by activity of both D1 and D2 receptors in the NAc. Further, cannabinoid type-1 (CB1) receptors in the NAc can also critically regulate motivated behavior. Thus, the main goal of this proposal is to use in vitro techniques, in particular whole-cell patch-clamp electrophysiology in NAc brain slices prepared from adult male rats to understand the molecular mechanisms through which endogenous cannabinoids (eCBs) and CB1 receptor activity could interact with dopamine receptors to enhance NAc firing activity. The long-term goal is to understand how NAcore CB1 and dopamine receptors interact to drive adaptive as well as pathological motivated behaviors, with the hope of developing novel therapeutic interventions for human neurological conditions. My preliminary data indicate that CB1 receptor antagonists prevent the D1/D2 cooperative enhancement of NAc core firing, suggesting that eCB activation of CB1 receptors could play a critical role in this process. However, the cellular mechanisms through which this occurs, especially the type of eCB which might contribute, remain unknown. Specific Aim 1 will examine the contribution of CB1 receptors to the D1/D2-mediated enhancement in NAc core firing. The role of CB1 receptors will be determined with several different CB1 receptor antagonists. The contribution of CB1 receptors will also be examined by investigating whether CB1 receptor activators can enhance NAc core firing alone, or whether interaction with a D1 or D2 receptor agonist is required to enhance firing. Specific Aim 2 will investigate intracellular pathways through which CB1 receptor activation could facilitate NAc core firing. In particular, the identity of the eCB which mediates the CB1/D1/D2 interaction will be examined using inhibitors of PLC, an enzyme critical for several eCB synthesis pathways, and inhibitors of FAAH and MGL, which hydrolyze the eCBs AEA and 2-AG. Also, neurons will be filled with AEA or 2-AG to determine whether these eCBs can increase NAc core firing alone or in combination with D1 or D2 receptor agonists. Together, these experiments will provide important information about the eCB that contributes critically to the D1/D2-mediated enhancement in NAc firing and the possible mechanism(s) through which dopamine and CB1 receptors could interact to enhance NAc firing activity. To facilitate achieving these goals, I will receive ongoing training and mentoring from my sponsor, other lab members, and outside collaborators in the design, implementation, and interpretation of my experiments, in the relevant research literature, and the preparation of my results for submission for publication. PUBLIC HEALTH RELEVANCE: Endogenous cannabinoids (endocannabinoids) modulate many diverse biological targets both in the central nervous system and in the periphery, and therefore play a critical role in many physiological processes such as pain, asthma, glaucoma, nausea, reproduction, immune system and cancer and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Pharmacological manipulation of this system may allow us to identify new therapeutic intervention for several neurological disorders while eliminating the undesirable side effects associated with cannabis. The results from this proposal may be useful in identifying novel signaling interactions that could represent possible pharmacological targets for treating addiction or other diseases.

描述（由申请人提供）：大量文献表明，多巴胺（DA）信号在丘脑核（NAc）中是成瘾相关和目标导向行为的关键介导因子。因此，有相当大的兴趣，了解DA可以改变NAc的发射活动和调节行为的分子机制。Bonci实验室以前的研究发现，DA D1和D2受体的协同激活增加了NAc神经元的放电。有趣的是，许多动机和成瘾相关的行为是由NAc中的D1和D2受体的活性维持的。此外，NAc中的大麻素1型（CB1）受体也可以严格调节动机行为。因此，本提案的主要目标是使用体外技术，特别是在从成年雄性大鼠制备的NAc脑切片中的全细胞膜片钳电生理学，以了解内源性大麻素（eCBs）和CB1受体活性可以与多巴胺受体相互作用以增强NAc放电活性的分子机制。长期目标是了解NAcore CB1和多巴胺受体如何相互作用以驱动适应性和病理性动机行为，希望为人类神经系统疾病开发新的治疗干预措施。 我的初步数据表明，CB1受体拮抗剂阻止D1/D2合作增强NAc核心放电，这表明CB激活CB1受体可能在这一过程中发挥关键作用。然而，这种情况发生的细胞机制，特别是可能起作用的eCB类型，仍然未知。具体目标1将检查CB1受体对D1/D2介导的NAc核心放电增强的贡献。将用几种不同的CB 1受体拮抗剂确定CB 1受体的作用。CB1受体的贡献也将通过研究CB1受体激活剂是否可以单独增强NAc核心放电，或者是否需要与D1或D2受体激动剂相互作用来增强放电来检查。具体目标2将研究CB1受体激活可促进NAc核心放电的细胞内途径。特别地，将使用PLC（一种对几种eCB合成途径至关重要的酶）的抑制剂和FAAH和MGL（其水解eCB AEA和2-AG）的抑制剂来检查介导CB 1/D1/D2相互作用的eCB的身份。此外，将用AEA或2-AG填充神经元，以确定这些eCB是否可以单独或与D1或D2受体激动剂组合增加NAc核心放电。总之，这些实验将提供有关eCB的重要信息，这些信息对D1/D2介导的NAc放电增强以及多巴胺和CB1受体相互作用以增强NAc放电活性的可能机制有重要贡献。 为了促进实现这些目标，我将接受我的赞助商，其他实验室成员和外部合作者的持续培训和指导，包括设计，实施和解释我的实验，相关的研究文献，以及准备我的结果提交出版。 公共卫生相关性：内源性大麻素（endocannabinoids）调节中枢神经系统和外周中的许多不同的生物靶标，因此在许多生理过程中起关键作用，例如疼痛、哮喘、青光眼、恶心、生殖、免疫系统和癌症以及神经退行性疾病如帕金森病和阿尔茨海默病。对该系统的药理学操作可能使我们能够为几种神经系统疾病确定新的治疗干预，同时消除与大麻相关的不良副作用。这一提议的结果可能有助于识别新的信号相互作用，这些信号相互作用可能代表治疗成瘾或其他疾病的可能药理学靶点。