Noradrenergic Regulation in the BNST

BNST 中的去甲肾上腺素能调节

基本信息

批准号：
9920688
负责人：
DANNY G WINDER
金额：
$ 35.27万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920688
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 conditioned place preference craving drug of abuse enhancing factor experimental study hyperpolarization-activated cation channel improved improved outcome new therapeutic target noradrenergic novel optogenetics postsynaptic prophylactic receptor recruit response success targeted treatment therapeutic candidate therapeutic development transmission process treatment strategy withdrawal-induced anxiety

项目摘要

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.

项目摘要成瘾是我们社会的巨大健康和经济负担。越来越多的文献表明大脑中的去甲肾上腺素在应力奖励相互作用中起关键作用，这可能介导关键行为对滥用药物的反应。以前未经批准的甲肾上腺素能神经元的群体成瘾，通过腹侧去甲肾上腺素能束（VNAB）投射的细胞被认为提供了钥匙去甲肾上腺素。大脑中VNAB的主要目标是一组核，称为扩展杏仁核。在前面的资金期间，我们确定了甲肾上腺素能的每个主要类别的行动受体的受体在质子末端的床核中的兴奋性突触传播，这是一个主要组成部分扩展的杏仁核。此外，我们确定了一种新型机制，甲肾上腺素能系统与皮质激素释放因子受体信号系统相互作用，以推动特定的募集 VTA投影神经元的种群。我们还确定了α2-肾上腺素受体的新作用调节兴奋性驱动器进入BNST。肾上腺素能的配体已被确定为治疗中潜在的预防治疗候选者瘾。尽管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谦虚。我们建议这部分是由于受体的许多不同作用由这些配体调节的调节，如果我们能够对受到寻求毒品关键的管制行动，我们可以微调治疗策略以增加效力。在这里，我们提出了实验，以描绘儿茶酚胺 - CRF信号传导相互作用调节应力诱导的可卡因寻求，而α2-肾上腺素受体诱导的抑制应力诱导的恢复原状。