Chronic Ethanol's Effects on Endocannabinoid Modulation of Neocrotical Up-states

慢性乙醇对新坏死上部状态内源性大麻素调节的影响

基本信息

批准号：
7806062
负责人：
Matthew Joseph Pava
金额：
$ 3.85万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-18 至 2011-09-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7806062
关键词：
Action Potentials Acute Affect Agonist Alcohol abuse Alcoholism Automobile Driving Behavior Behavioral Biochemical Biological Assay Brain region Cells Chronic Cognitive deficits Consumption Dental crowns Dependence Development Disease Dopamine Electroencephalography Electrophysiology (science)Endocannabinoids Ethanol Exposure to Glutamates Goals Human Immunoblot Analysis In Vitro Individual Knock-out Knockout Mice Laboratories Lead Maintenance Measurement Measures Mediating Membrane Potentials Modality Modeling Mus N-Methylaspartate Neuraxis Neurobiology Neuroblastoma Neuromodulator Neurons Neurotransmitters Pathology Pathway interactions Patients Pattern Pharmaceutical Preparations Physiological Play Prefrontal Cortex Presynaptic Terminals Protocols documentation Rattus Regulation Relapse Research Rewards Role Self-Administered Sensory Signal Pathway Signal Transduction Slice Source Specificity Synapses Synaptic Membranes Synaptic Potentials Synaptic Transmission System Techniques Testing Time Tissues Training Trauma Up-Regulation Withdrawal Work addiction alcohol abuse therapy alcohol effect alcohol exposure cost drug seeking behavior frontal lobe hippocampal pyramidal neuron in vivo information processing meetings neurophysiology neurotransmitter release patch clamp problem drinker receptor reconstitution research study response reward processing therapeutic target vapor

项目摘要

DESCRIPTION (provided by applicant): Each year, the disease and trauma associated with alcohol abuse disorders result in tremendous financial and human cost worldwide. In individuals, chronic consumption of high volumes of ethanol produces neuroadaptive changes that alter the function of a variety of brain regions. Classically, much research has focused on the role played by alterations to reward signaling pathways (e.g. the mesolimbic dopamine pathway) in the manifestation and maintenance of addictive disorders. However, more recently research has begun to focus on the neurobiological substrates of cognitive deficits commonly displayed by substance abusing individuals, and evidence is accumulating that frontal cortical regions like the prefrontal cortex (PFC) are damaged or dysfunctional in patients meeting criteria for alcohol abuse and dependence disorders. Networks of cortical neurons serve to process information from sensory modalities and other brain regions, and when network function is sufficiently altered or diminished, behavioral abnormalities like the inability to control certain behaviors emerge. In fact, a hallmark of addiction pathology is the inability of the dependent individual to control their own drug-seeking behavior. One source of altered network function could be changes to neuromodulatory systems that regulate cortical activity. Endocannabinoids (eCB) are a class of neuromodulators that regulate PFC function, and the eCB system is itself perturbed by chronic ethanol exposure. eCBs are retrograde neurotransmitters that are released In response to cell depolarization, and their major receptor in the central nervous system is the CBI receptor. In the cortex, CBI is localized to presynaptic terminals at both glutamatergic and GABAergic synapses, and activation of CBI at either type of synapse results in decreased release of the respective neurotransmitter. Additionally, the expression and function of CB1 is diminished after chronic ethanol treatment. The long-term goal of the proposed study is to characterize how ethanol-induced changes in CBI expression and function alter cortical network activity. This study will employ a PFC explant culture model using tissue from CBI knockout mice and techniques including electrophysiology and biochemical assays. The specific aims are: (1) Characterize the contribution of the eCB system toward the regulation of up-states in organotypic cultures of PFC, and (2) test the hypothesis that alterations in eCB signaling after chronic EtOH exposure contribute to enhanced up-states in organotypic cultures of PFC. Findings from this work may help to reduce relapse in abstinent individuals by elucidating therapeutic targets for the treatment of alcohol abuse and dependence.

描述（由申请人提供）：每年，与酒精滥用障碍相关的疾病和创伤都会在全世界造成巨大的经济和人力成本。对于个体来说，长期摄入大量乙醇会产生神经适应性变化，从而改变多个大脑区域的功能。传统上，许多研究都集中在奖励信号通路（例如中脑边缘多巴胺通路）的改变在成瘾性疾病的表现和维持中所发挥的作用。然而，最近的研究开始关注药物滥用者通常表现出的认知缺陷的神经生物学基础，并且越来越多的证据表明，在符合酗酒和酗酒标准的患者中，前额皮质（PFC）等额叶皮层区域受损或功能失调。依赖性障碍。皮质神经元网络用于处理来自感觉方式和其他大脑区域的信息，当网络功能充分改变或减弱时，就会出现行为异常，例如无法控制某些行为。事实上，成瘾病理学的一个标志是依赖者无法控制自己的吸毒行为。网络功能改变的来源之一可能是调节皮质活动的神经调节系统的变化。内源性大麻素 (eCB) 是一类调节 PFC 功能的神经调节剂，而 eCB 系统本身会受到长期乙醇暴露的干扰。 eCB 是响应细胞去极化而释放的逆行神经递质，它们在中枢神经系统中的主要受体是 CBI 受体。在皮质中，CBI 定位于谷氨酸能和 GABA 能突触的突触前末端，并且任一类型突触的 CBI 激活都会导致相应神经递质的释放减少。此外，长期乙醇处理后，CB1 的表达和功能会减弱。拟议研究的长期目标是描述乙醇诱导的 CBI 表达和功能变化如何改变皮质网络活动。本研究将采用 PFC 外植体培养模型，使用 CBI 敲除小鼠的组织以及电生理学和生化测定等技术。具体目标是：(1) 描述 eCB 系统对 PFC 器官型培养物中上状态调节的贡献，以及 (2) 检验长期 EtOH 暴露后 eCB 信号传导的变化有助于增强上状态的假设在 PFC 的器官型培养物中。这项工作的结果可能有助于通过阐明治疗酒精滥用和依赖的治疗目标来减少戒酒者的复发。