Role of Anandamide in a Rodent Model of an Alcohol Use Disorder

Anandamide 在酒精使用障碍啮齿动物模型中的作用

• 批准号: 8155329
• 负责人: Daniel James Liput
• 金额: $ 2.73万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8155329
• 关键词: 2-arachidonylglycerol; Address; Agonist; Alcoholism; Alcohols; American; Attenuated; Autoradiography; Behavioral; Brain; Brain Injuries; Brain region; Cannabinoids; Cells; Characteristics; Chronic; Cognitive; DSM-IV; Dose; Down-Regulation; Endocannabinoids; Enzymes; Functional disorder; Future; Glutamates; Goals; Heavy Drinking; High Pressure Liquid Chromatography; Hippocampus (Brain); Immunoblotting; Impairment; Individual; Inflammation; Investigation; Ischemia; Knockout Mice; Lead; Link; Literature; Measures; Mediating; Modeling; Nerve Degeneration; Oxidative Stress; Parahippocampal Gyrus; Parkinson Disease; Pathologic; Pathology; Pharmacologic Substance; Play; Population; Property; Proteins; Public Health; Research; Research Design; Rodent Model; Role; Signal Transduction; Staining method; Stains; Structure; System; Techniques; Testing; Tissues; Traumatic Brain Injury; United States; addiction; alcohol abuse therapy; alcohol exposure; alcohol response; alcohol use disorder; anandamide; cannabinoid receptor; dentate gyrus; excitotoxicity; executive function; fatty acid amide hydrolase; fluoro jade; inhibitor/antagonist; insight; meetings; neuroprotection; neurotoxicity; novel; novel strategies; phosphoric diester hydrolase; prevent; problem drinker; progressive neurodegeneration; public health relevance; receptor; receptor density; receptor expression; research study; response; treatment strategy; 2-arachidonylglycerol; Address; Agonist; Alcoholism; Alcohols; American; Attenuated; Autoradiography; Behavioral; Brain; Brain Injuries; Brain region; Cannabinoids; Cells; Characteristics; Chronic; Cognitive; DSM-IV; Dose; Down-Regulation; Endocannabinoids; Enzymes; Functional disorder; Future; Glutamates; Goals; Heavy Drinking; High Pressure Liquid Chromatography; Hippocampus (Brain); Immunoblotting; Impairment; Individual; Inflammation; Investigation; Ischemia; Knockout Mice; Lead; Link; Literature; Measures; Mediating; Modeling; Nerve Degeneration; Oxidative Stress; Parahippocampal Gyrus; Parkinson Disease; Pathologic; Pathology; Pharmacologic Substance; Play; Population; Property; Proteins; Public Health; Research; Research Design; Rodent Model; Role; Signal Transduction; Staining method; Stains; Structure; System; Techniques; Testing; Tissues; Traumatic Brain Injury; United States; addiction; alcohol abuse therapy; alcohol exposure; alcohol response; alcohol use disorder; anandamide; cannabinoid receptor; dentate gyrus; excitotoxicity; executive function; fatty acid amide hydrolase; fluoro jade; inhibitor/antagonist; insight; meetings; neuroprotection; neurotoxicity; novel; novel strategies; phosphoric diester hydrolase; prevent; problem drinker; progressive neurodegeneration; public health relevance; receptor; receptor density; receptor expression; research study; response; treatment strategy

DESCRIPTION (provided by applicant): Alcohol Use Disorders (AUDs) represent a major public health problem in the United States with over 8% of Americans meeting the DSM-IV criteria for an AUD. Excessive alcohol intake causes progressive neurodegeneration that often leads to cognitive and behavioral deficits, and subsequently alcoholism. To date, there are no approved therapies for alcohol-induced neurodegeneration, thus warranting investigation into novel mechanisms of neuroprotection. The endocannabinoid system has been implicated as a novel neuroprotective system in a variety brain injury models. Studies suggest that the endocannabinoid anandamide (AEA) is elevated after ischemic and traumatic brain injuries, which affords endogenous neuroprotection. However it is not know if AEA affords similar neuroprotection for alcohol-induced neurodegeneration. Therefore, the guiding hypothesis for this present proposal is that AEA tone is amplified by alcohol-induced brain damage as a neuroprotective mechanism and therefore potentiating AEA tone by inhibiting AEA degradation affords additional neuroprotection. Specific Aim 1 will utilize HPLC/MS/MS techniques to assess levels of AEA in the entorhinal/perirhinal cortex and hippocampus, two regions susceptible to alcohol-induced neurodegeneration in a binge model of an AUD. Additionally, immunoblotting will be used to elucidate the mechanism of altered AEA tone. Specific Aim 2 will utilize receptor autoradiography to assess cannabinoid 1 (CB1) receptor expression during a binge-alcohol exposure paradigm in the brain regions mentioned above. This will allow us to gain insight to the relationship between CB1 receptors and elevations of AEA in context of neuroprotection, as AEA may cause CB1 down-regulation. Aim 3 will consist of two experiments to evaluate the efficacy of enhancing AEA tone, by inhibiting fatty acid amide hydrolase (FAAH), to attenuate alcohol- induced neurodegeneration. Experiment 1 will determine an optimum dose of URB-595, a FAAH inhibitor, to attenuate alcohol-induced neurodegeneration in the entorhinal/perirhinal cortex and ventral dentate gyrus of the hippocampus using fluoro-jade b stain. The second experiment will test whether AEA neuroprotection is mediated through the CB1 receptor using the CB1 receptor antagonist SR-141716. These studies will provide important insight into the effects of binge alcohol administration on the endocannabinoid system as well as neuroprotective properties of the endocannabinoid system in alcohol-induced brain damage. These studies will lead to future investigation into the specific mechanisms linking the endocannabinoid system to alcohol- induced neurodegeneration. Additionally, these results will lead to novel approaches and/or novel pharmaceutical agents for the treatment of neurodegeneration linked to AUD's. PUBLIC HEALTH RELEVANCE: Current treatments for alcohol use disorders commonly referred to as alcoholism, although effective for some, are less than adequate. With over 8% percent of the population currently suffering from an alcohol use disorder, it is essential that new therapies become available for these individuals. The proposed studies will give insight into novel treatment strategies for the treatment of alcohol use disorders, specifically for the treatment of alcoholic brain damage.

描述（由申请人提供）：酒精使用障碍（AUDS）代表了美国的一个主要公共卫生问题，其中超过8％的美国人满足了AUD的DSM-IV标准。过量的酒精摄入会导致进行性神经退行性变化，这通常会导致认知和行为缺陷，随后是酒精中毒。迄今为止，尚无对酒精引起的神经退行性的批准疗法，因此需要研究神经保护的新机制。内源性大麻素系统已被认为是一种新型的脑损伤模型中的新神经保护系统。研究表明，缺血性和创伤性脑损伤后，内源性大麻素吻合胺（AEA）升高，可提供内源性神经保护作用。但是，不知道AEA是否对酒精诱导的神经退行性产生类似的神经保护作用。因此，本建议的指导假设是，AEA张力通过酒精诱导的脑损伤作为一种神经保护机制而放大，因此通过抑制AEA降解可以增强AEA张力，从而提供了其他神经保护作用。具体的目标1将利用HPLC/MS/MS技术来评估内嗅/周围皮层和海马的AEA水平，这两个区域在AUD的暴饮暴食模型中易受酒精诱导的神经变性。另外，将使用免疫印迹来阐明改变AEA音调的机制。具体的目标2将利用受体自显影术在上述大脑区域的暴饮暴食暴露范式中评估大麻素1（CB1）受体表达。这将使我们能够深入了解CB1受体与AEA在神经保护范围内的升高之间的关系，因为AEA可能会导致CB1下调。 AIM 3将包括两个实验，以通过抑制脂肪酸酰胺水解酶（FAAH）来评估增强AEA张力的功效，以减轻酒精诱导的神经变性。实验1将确定最佳剂量的FAAH抑制剂URB-595，以使用氟-jade b stain抑制酒精诱导的神经变性。第二个实验将使用CB1受体拮抗剂SR-141716测试AEA神经保护是否通过CB1受体介导。这些研究将为酒精饮酒对内源性大麻素系统的影响以及内源性大麻素系统对酒精引起的脑损伤的影响提供重要的见解。这些研究将导致未来研究将内源性大麻素系统与酒精诱导的神经变性联系起来的特定机制。此外，这些结果将导致新的方法和/或新型药物治疗与AUD相关的神经变性。 公共卫生相关性：当前对酒精使用障碍的治疗方法通常称为酒精中毒，尽管对某些人有效，但还不够。 目前有超过8％的人口患有酒精疾病，因此必须为这些人提供新的疗法。拟议的研究将洞悉用于治疗酒精使用障碍的新型治疗策略，特别是用于治疗酒精性脑损伤。