Mechanisms underlying the influence of beta-endorphin on EtOH reward, aversion, a

β-内啡肽对乙醇奖赏、厌恶、酒精影响的机制

• 批准号: 7194340
• 负责人: JUDITH E GRISEL
• 金额: $ 21.45万
• 依托单位: FURMAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-10 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194340
• 关键词: Abbreviations; Affect; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Anabolism; Animal Model; Behavioral; Biological Assay; Biological Factors; Brain; Dependence; Development; Disease; Endorphins; Ethanol; Genetic; Genetically Engineered Mouse; Gonadal Hormones; Gonadal Steroid Hormones; Heterozygote; Human; Knowledge; Lead; Link; Literature; Measures; Mediating; Mus; Opioid; Opioid Peptide; Peptides; Play; Population; Property; Reporting; Rewards; Risk; Role; Series; Societies; System; Testosterone; Thinking; alcohol effect; alcohol exposure; alcohol response; alcohol sensitivity; beta-Endorphin; college; neuroadaptation; neurochemistry; problem drinker; relating to nervous system; research study; sex

DESCRIPTION (provided by applicant): Opioid peptides contribute to the effects of ethanol and play a role in the development of alcoholism. For example, human populations with a genetic propensity toward alcohol abuse and dependence are reported to differ with respect to ethanol- stimulated release of b-endorphin, and these differences may affect the pharmacological properties of alcohol to contribute toward the disease state. The experiments in this proposal utilize an animal model to investigate the relationship between b-endorphin and alcohol sensitivity. We've found that genetically engineered mice that lack the ability to synthesize the peptide b-endorphin differ markedly in several measures of alcohol sensitivity, including ethanol-mediated reward, aversion and neural adaptation. Mirroring epidemiological findings from alcoholic populations, the effects of b-endorphin on alcohol response often appears to be sex- dependent. Moreover, we have found that gonadal hormones such as testosterone regulate the effect of b-endorphin on alcohol sensitivity. Despite the clear evidence linking alcohol response and b-endorphin, to date, studies reported in the literature have been correlational. In order to elucidate the mechanisms underlying this differential sensitivity we plan a series of comprehensive behavioral studies in mice with varying levels of b-endorphin. These will systematically vary ethanol exposure, b-endorphin level and sex/hormone status. In addition, neurochemical assays will be used to begin uncovering the neural consequences of low or absent b-endorphin that result in modified alcohol sensitivity. Finally, the effect of gonadal steroid hormones in modulating the ethanol's action on brain substrates will be explored. It is hoped that these studies will lead to a greater understanding of the relationship between b-endorphin and alcohol and thereby contribute to our knowledge of the mechanisms underlying human alcohol dependence. Although alcoholism and its consequences have devastating implications throughout the world and on virtually all aspects of human society, the causes are still largely unknown. The opioid peptide system is thought to be one important biological factor contributing to a liability for developing alcoholism and we use an animal model to better understand the mechanisms by which opioids modulate this risk.

描述（由申请人提供）：阿片肽有助于乙醇的作用，并在酒精中毒的发展中发挥作用。例如，据报道，具有酒精滥用和依赖遗传倾向的人群在乙醇刺激的β-内啡肽释放方面存在差异，这些差异可能会影响酒精的药理学性质，从而导致疾病状态。本实验利用动物模型研究β-内啡肽与酒精敏感性的关系。我们发现，缺乏合成b-内啡肽能力的基因工程小鼠在酒精敏感性的几个指标上存在显著差异，包括乙醇介导的奖励，厌恶和神经适应。从酗酒人群的流行病学调查结果来看，β-内啡肽对酒精反应的影响往往表现出性别依赖性。此外，我们还发现，性腺激素如睾酮调节β-内啡肽对酒精敏感性的影响。尽管有明确的证据表明酒精反应与b-内啡肽有关，但迄今为止，文献中报道的研究一直是相关的。为了阐明这种差异敏感性的机制，我们计划在不同水平的b-内啡肽的小鼠中进行一系列全面的行为研究。这些将系统地改变乙醇暴露，b-内啡肽水平和性/激素状态。此外，神经化学分析将用于开始揭示导致酒精敏感性改变的低或缺乏b-内啡肽的神经后果。最后，将探讨性腺类固醇激素在调节乙醇对脑基质的作用中的作用。希望这些研究将导致更好地了解b-内啡肽和酒精之间的关系，从而有助于我们了解人类酒精依赖的机制。虽然酗酒及其后果对全世界和人类社会的几乎所有方面都产生了毁灭性的影响，但其原因在很大程度上仍不为人所知。阿片肽系统被认为是一个重要的生物学因素，有助于发展酒精中毒的责任，我们使用动物模型，以更好地了解阿片类药物调节这种风险的机制。