Noradrenergic Regulation in the BNST

BNST 中的去甲肾上腺素能调节

• 批准号: 9917488
• 负责人: DANNY G WINDER
• 金额: $ 4.14万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917488
• 关键词: Adrenergic Agents; Adrenergic Agonists; Adrenergic Antagonists; Adrenergic Receptor; Amygdaloid structure; Arousal; Automobile Driving; Autoreceptors; Behavior; Brain; Catecholamines; Cell Nucleus; Cells; Clinical; Cocaine; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Effectiveness; Electrophysiology (science); FOS gene; Financial Hardship; Funding; Glutamates; Guanfacine; Health; Human; Hypothalamic structure; Infusion procedures; Lead; Ligands; Literature; Location; Mediating; Modeling; Motivation; Mus; Neurons; Norepinephrine; Outcome; Pain; Pathway interactions; Pharmaceutical Preparations; Play; Population; Process; Propranolol; Receptor Activation; Receptor Signaling; Regulation; Relapse; Reporter; Rewards; Rodent; Role; Signal Transduction; Slice; Societies; Source; Stress; Structure of terminal stria nuclei of preoptic region; Synaptic Transmission; System; Testing; Therapeutic; Viral; addiction; behavioral response; beta-adrenergic receptor; brain circuitry; cell type; cocaine exposure; craving; drug of abuse; enhancing factor; experimental study; hyperpolarization-activated cation channel; improved; improved outcome; new therapeutic target; noradrenergic; novel; optogenetics; postsynaptic; preference; prophylactic; receptor; recruit; response; success; targeted treatment; therapeutic candidate; therapeutic development; transmission process; treatment strategy; withdrawal-induced anxiety

Project Summary Addiction is a tremendous health and financial burden on our society. A growing literature indicates that norepinephrine in the brain plays a key role in stress-reward interactions that may mediate key behavioral responses to drugs of abuse. A previously unappreciated group of noradrenergic neurons in the field of addiction, cells that project through the ventral noradrenergic bundle (VNAB), are thought to supply the key norepinephrine. The primary target of the VNAB in the brain is a group of nuclei referred to as the extended amygdala. In the previous funding periods, we identified actions of each of the major classes of noradrenergic receptors on excitatory synaptic transmission in the bed nucleus of the stria terminalis, a major component of the extended amygdala. Moreover, we identified a novel mechanism whereby the noradrenergic system interacts with the corticotropin releasing factor receptor signaling system to drive recruitment of specific populations of VTA projecting neurons. We also identified novel actions of alpha2-adrenergic receptors in regulation of excitatory drive into the BNST. Adrenergic ligands have been identified as potential prophylactic therapeutic candidates in treating addiction. While results in human studies have been encouraging, their overall success in improving outcomes has been modest. We propose that this is in part due to the many disparate actions that the receptors regulated by these ligands regulate, and that if we could develop a more specific understanding of the regulated actions that were key to drug-seeking, we could fine tune treatment strategies to increase effectiveness. Here, we propose experiments to delineate specific pathways through which catecholamine- CRF signaling interactions regulate stress-induced cocaine seeking, and alpha2-adrenergic receptor-induced suppression of stress-induced reinstatement.

项目摘要 成瘾对我们的社会来说是一个巨大的健康和经济负担。越来越多的文献表明， 大脑中的去甲肾上腺素在压力-奖励相互作用中起着关键作用， 对滥用药物的反应。肾上腺素能神经元领域中一组以前未被认识到的去甲肾上腺素能神经元 成瘾，通过腹侧去甲肾上腺素能束（VNAB）投射的细胞，被认为提供了关键 去甲肾上腺素VNAB在脑中的主要靶点是一组称为延伸核团的核团。 杏仁核在以前的资助期间，我们确定了每种主要的去甲肾上腺素能受体的作用， 受体对兴奋性突触传递在床核的终纹，一个主要组成部分， 延伸的杏仁核此外，我们发现了一种新的机制，即去甲肾上腺素能系统 与促肾上腺皮质激素释放因子受体信号系统相互作用， VTA投射神经元的群体。我们还发现了α 2-肾上腺素能受体在脑内的新作用。 调节进入BNST的兴奋性驱动。 肾上腺素能配体已被确定为治疗糖尿病的潜在预防性治疗候选物。 成瘾虽然人类研究的结果令人鼓舞，但它们在改善结果方面的总体成功 一直很谦虚我们认为，这部分是由于受体的许多不同的行动， 如果我们能对这些配体的调节有更具体的了解， 监管行动是寻求毒品的关键，我们可以微调治疗策略， 有效性在这里，我们提出实验来描绘特定的途径，通过它的儿茶酚胺- CRF信号相互作用调节应激诱导的可卡因寻求和α 2-肾上腺素能受体诱导的 抑制压力诱发的恢复。