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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

基本信息

批准号：
8309317
负责人：
Taban none Seif
金额：
$ 4.77万
依托单位：
ERNEST GALLO CLINIC AND RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309317
关键词：
2-arachidonylglycerol AM 251 Adult Adverse effects Agonist Alcohol consumption Alcohols Alzheimer&apos 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 G-protein Beta gamma GTP-Binding Protein alpha Subunits, Gs 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 abstracting 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 receptor research study response rimonabant

项目摘要

6. Project Summary/Abstract 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 ¿ 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 ¿¿ will investigate intracellular pathways through which CB1 receptor activation could facilitates NAc core firing. In particular, the identify 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.

6. 项目总结/文摘