Synaptic and Behavioral Correlates of Adeonsinergic Signaling in the BLA

BLA 中腺苷酸信号传导的突触和行为相关性

• 批准号: 8452781
• 负责人: Andrew Ryan Rau
• 金额: $ 4.22万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-22 至 2015-08-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452781
• 关键词: Acute; Adenosine; Adolescent; Agonist; Alcohol consumption; Alcoholism; Amygdaloid structure; Animal Model; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Attenuated; Behavior; Behavioral; Behavioral Assay; Brain region; Characteristics; Chronic; Clinical; Comorbidity; Complex; Data; Development; Disease; Doctor of Philosophy; Ethanol; Fellowship; Funding; Glutamates; Goals; Health Sciences; Housing; Human; Individual; Investigation; Knowledge; Laboratories; Lead; Life Stress; Link; Literature; Mediating; Modeling; Monkeys; National Research Service Awards; Neuraxis; Neurobiology; Neuromodulator; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Physiological; Physiology; Play; Property; Publishing; Purinergic P1 Receptors; Rattus; Regulation; Research; Research Training; Rodent; Rodent Model; Role; Self Administration; Series; Signal Transduction; Site; Social isolation; Specificity; Synapses; Synaptic Transmission; System; Testing; Therapeutic; Time; Treatment Protocols; Universities; Withdrawal; Work; addiction; adenosine receptor activation; alcohol effect; alcohol exposure; alcohol use disorder; analog; base; catalyst; design; effective therapy; follow-up; forest; insight; interest; neurotransmission; novel; postsynaptic; pre-doctoral; preclinical study; presynaptic; receptor; relating to nervous system; research study; transmission process

DESCRIPTION (provided by applicant): This application for a Ruth L. Kirschstein NRSA for Individual Predoctoral Fellowship is submitted by Andrew R. Rau in order to seek funding for research training under the guidance of Jeff L. Weiner, Ph.D. in the Department of Physiology and Pharmacology at Wake Forest University Health Sciences. Research in the laboratory of Dr. Weiner is focused on unraveling the mechanisms responsible for the complex synaptic and behavioral effects of ethanol and anxiety related disorders. The research studies proposed in this application are intended to, for the first time characterize the role of adenosine (ADO) in regulating synaptic transmission within the basolateral amygdala (BLA). Moreover, these studies will further our understanding of adenosine's role in the neurobiological underpinnings associated with a model of early life stress that is associated with marked increases in anxiety-like behavior and ethanol consumption. Adenosine generally exerts its inhibitory effects by activating presynaptic A1 receptors which inhibit glutamate release. To that end, it would be of critical therapeutic benefit if this was the case in the BLA, as excessive excitability in this region has been directly linked to the manifestation of anxiety-like behaviorsin rodents, monkeys, and humans. Therefore this proposal outlines a series of experiments designed to characterize ADO's actions in the BLA and to investigate the behavioral outcomes of intra-BLA delivery of ADO agonists and antagonists. Briefly, Aim 1 will follow up on preliminary findings to identify the ADO receptor subtypes that mediate ADO modulation of BLA synaptic transmission. This aim will also test the hypothesis that tonic adenosinergic tone actively regulates excitatory transmission in the BLA. This aim will also test the hypothesis that adenosinergic tone is disrupted following adolescent social isolation, a model of early life stress that engenders increases in anxiety-like behavior as well as increases in ethanol consumption. Building upon this aim, Aim 2 will use behavioral assays to determine the ability of ADO, delivered directly into the BLA, to attenuate the increases in anxiety-like behavior and ethanol consumption brought on by social isolation. These studies will significantly advance our understanding of ADO signaling in the BLA and possibly identify novel neural substrates linking early life stress and increased anxiety-like behaviors and ethanol drinking. Moreover, insights gathered from these investigations may reveal promising new targets for development of novel pharmacotherapeutics for treating addiction and anxiety disorders. PUBLIC HEALTH RELEVANCE: Despite robust evidence that adenosine modulates excitability throughout the central nervous system, its effects on the basolateral amygdala a region critically involved in anxiety and alcohol use disorders - have yet to be investigated. This proposal, if funded, will investigate, for the first time the synaptic underpinnings of adenosinergic signaling in the basolateral amygdala. Additionally, this study will provide initial insights into the ability of adenosine receptor activation within the basolateral amygdala to mitigate the increases in anxiety-like behavior and ethanol consumption seen in a model of rodent early life stress and help to formulate research strategies that will advance and expand our current treatment regimens for anxiety and addiction disorders.

描述（由申请人提供）：本申请露丝L。Kirschstein NRSA个人博士前奖学金由Andrew R. 劳为了寻求研究培训的指导下，杰夫L。Weiner博士 在维克森林大学健康科学的生理学和药理学系。韦纳博士实验室的研究重点是解开乙醇和焦虑相关疾病的复杂突触和行为影响的机制。本申请中提出的研究旨在首次表征腺苷的作用 (ADO)在调节基底外侧杏仁核（BLA）内的突触传递。 此外，这些研究将进一步了解腺苷在与早期生活压力模型相关的神经生物学基础中的作用，该模型与焦虑样行为和乙醇消耗的显着增加相关。腺苷通常通过激活抑制谷氨酸释放的突触前A1受体发挥其抑制作用。为此，如果这是BLA的情况，这将是至关重要的治疗益处，因为该区域的过度兴奋与啮齿动物，猴子和人类的焦虑样行为的表现直接相关。 因此，本提案概述了一系列旨在表征ADO在BLA中的作用并研究ADO激动剂和拮抗剂在BLA内递送的行为结果的实验。 简言之，目标1将跟进初步发现，以确定ADO受体亚型介导的ADO调制BLA突触传递。这一目的也将测试的假设，紧张性腺苷能紧张积极调节兴奋性传输的BLA。这一目标也将测试的假设，即腺苷能紧张被破坏后，青少年的社会隔离，一个模型的早期生活压力，产生增加的焦虑样行为，以及增加乙醇消费。基于这一目标，目标2将使用行为测定来确定ADO的能力，直接输送到BLA，以减轻焦虑样行为和乙醇消费的增加所带来的社会隔离。 这些研究将显著推进我们对BLA中ADO信号传导的理解，并可能确定将早期生活压力与焦虑样行为增加和乙醇饮用联系起来的新型神经底物。此外，从这些调查中收集的见解可能会揭示有希望的新目标，用于开发治疗成瘾和焦虑症的新型药物治疗药物。 公共卫生相关性：尽管有强有力的证据表明腺苷调节整个中枢神经系统的兴奋性，但它对基底外侧杏仁核（一个与焦虑和酒精使用障碍密切相关的区域）的影响还有待研究。这项提案如果获得资助，将首次研究基底外侧杏仁核中腺苷能信号的突触基础。此外，这项研究将提供对基底外侧杏仁核内腺苷受体激活能力的初步了解，以减轻啮齿动物早期生活压力模型中出现的焦虑样行为和乙醇消耗的增加，并有助于制定研究策略，以推进和扩大我们目前的焦虑和成瘾性疾病治疗方案。