Stress and alcohol drinking: early life dysregulation of neuropeptides

压力和饮酒：生命早期神经肽的失调

• 批准号: 8525746
• 负责人: Lara Stephanie Hwa
• 金额: $ 4.22万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-11 至 2015-09-10
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525746
• 关键词: Acute; Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animals; Behavior; Behavioral; Brain; CRF receptor type 1; Caring; Child; Complement; Complex; Corticotropin-Releasing Hormone; Dialysis procedure; Dopamine; Drug abuse; Early-life trauma; Excision; Functional disorder; Genes; Genetic; Genetic Suppression; Genetic Techniques; Genetic screening method; Heavy Drinking; Hormones; Hour; Human; Individual; Infant; Laboratories; Life; Life Stress; Link; Measures; Methods; Microdialysis; Microinjections; Molecular Biology; Molecular Genetics; Mus; Neuropeptides; Neurotransmitters; Nucleus Accumbens; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Prefrontal Cortex; Preparation; Prevention; Procedures; Property; Prosencephalon; Proteins; RRM1 gene; Research; Research Personnel; Rewards; Role; Scientific Advances and Accomplishments; Signal Transduction; Site; Social Environment; Stress; Structure; Techniques; Technology; Testing; Training; Transcript; Transgenes; Translating; Ventral Tegmental Area; alcohol availability; alcohol use disorder; alcoholism therapy; cognitive function; drinking; drinking behavior; innovation; interest; male; maternal separation; monoamine; mouse model; mutant; neglect; neural circuit; neuroadaptation; novel; prevent; problem drinker; public health relevance; pup; relating to nervous system; research study; social; social stress; stressor; theories; transmission process

DESCRIPTION (provided by applicant): The link between stress and alcohol drinking is complex, but some crucial neuroadaptations in stress pathways are beginning to be understood. The current proposal explores the neural substrates of how early life stress renders mice vulnerable to excessive alcohol drinking in adulthood. One interesting neuropeptide that can be disrupted is the stress neuropeptide corticotropin-releasing factor (CRF) in the brain. CRF may be an important regulatory hormone in social alcohol drinkers, but it is the dysfunction of CRF that may develop during alcohol dependence. CRF can be found in distinct brain structures, like the ventral tegmental area (VTA). The VTA is one site that can signal for the rewarding properties of drugs and communicate stress through the neurotransmitter dopamine (DA). The dysregulation of the CRF network may be crucial to influencing alcohol drinking driven by stress. To critically examine these theories, researchers can use maternal separation stress (MSS) in mice to induce neuroadaptations to increase alcohol drinking in adulthood. In the first set of experiments, mouse pups are separated from maternal care for 3 hours per day for 2 weeks. Later in adulthood, mice are given intermittent access to alcohol, an advantageous method to test escalated voluntary alcohol drinking. We will then measure if pharmacological treatment with CRF-R1 antagonists into the VTA can prevent intensified stress-altered DA impulse flow. Changes in DA as a result of alcohol drinking are measured with microdialysis in the prefrontal cortex (PFC), a terminal region of the VTA, in stressed mice vs. unstressed mice. CRF protein in the brain will also be measured after MSS and after escalated alcohol drinking. In a second group of experiments, researchers test if genetic prevention of forebrain CRF-R1 can influence alcohol drinking. Mice lacking CRF-R1 gene transcript in the forebrain also undergo MSS, alcohol drinking, and dialysis to assess DA output. Ultimately, these methods allow for site-specific manipulations to study CRF modulation of the VTA-PFC pathway in stress-escalated behavior. The pharmacological and genetic approaches not only complement each other, but also allow for considerable training potential. Altogether, identifying the crucial pathways in stress-escalated drinking would advance scientific understanding of the mechanisms behind the transition to alcoholism. Findings from the proposed experiments may reveal those interactions between genes and the social environment that differentiates social use from excessive drinking. Ultimately, targeted treatment for alcohol use disorders may include pharmacotherapy and management of early life stress.

描述（由申请人提供）：压力和饮酒之间的联系很复杂，但是在压力途径中，一些至关重要的神经照射开始被理解。当前的提案探讨了生命早期压力如何使小鼠在成年后容易饮酒的小鼠的神经基质。可能破坏的一种有趣的神经肽是大脑中应力神经肽皮质激素释放因子（CRF）。 CRF可能是社交酒精饮酒者中重要的调节激素，但在酒精依赖期间可能会出现CRF的功能障碍。 CRF可以在不同的大脑结构中找到，例如腹侧对盖区域（VTA）。 VTA是一个可以发出奖励药物特性并通过神经递质多巴胺（DA）传达应力的部位。 CRF网络的失调可能对影响压力驱动的饮酒至关重要。为了批判性检查这些理论，研究人员可以使用小鼠的母体分离应力（MSS）诱导神经适应性，以增加成年后的饮酒。在第一组实验中，小鼠幼崽每天与母体护理分开3小时，持续2周。成年后的晚些时候，使小鼠间歇性地获得酒精，这是测试升级自愿饮酒的有利方法。然后，我们将测量使用CRF-R1拮抗剂进入VTA的药理学治疗是否可以防止改变压力的DA脉冲流动。饮酒导致DA的变化是用微透析在额叶皮层（PFC）（PFC）（VTA的末端区域）与无压力小鼠相比的末端区域的。在MSS和饮酒升级后，大脑中的CRF蛋白也将测量。在第二组实验中，研究人员测试了前脑CRF-R1的遗传预防是否会影响饮酒。在前脑缺乏CRF-R1基因转录本的小鼠还接受MSS，饮酒和透析以评估DA产量。最终，这些方法允许特定地点的操作研究应力提升行为中VTA-PFC途径的CRF调制。药理学和遗传方法不仅相互补充，而且还具有相当大的训练潜力。总体而言，确定压力提升的饮酒中的关键途径将提高对过渡到酒精中毒背后的机制的科学理解。提出的实验的发现可能揭示了基因与社会环境之间的相互作用，这些社会环境将社会用途与过度饮酒区分开。最终，针对酒精使用障碍的有针对性治疗可能包括药物治疗和早期生活压力的治疗。