Activity of brainstem neurons

脑干神经元的活动

基本信息

批准号：
7797620
负责人：
Nae J Dun
金额：
$ 33.75万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-05-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7797620
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione Abbreviations Acids Address Adrenergic Agents Adult Affect Aftercare Amines Animal Model Animals Area Arrhythmia Blood Pressure Brain Stem Cardiovascular Abnormalities Cardiovascular Diseases Cardiovascular system Cell Nucleus Cells Chemicals Chemosensitization Chest Clinical Cocaine Cocaine Abuse Cocaine Users Cyclopentane D Aspartate Data Dicarboxylic Acids Dopamine Dopamine Uptake Inhibitors Dose Drug usage Epidemiology Event Excitatory Amino Acid Antagonists Excitatory Postsynaptic Potentials Functional disorder Fura-2 Glutamate Receptor Glutamates Goals Hanks Balanced Salt Solution Heart Diseases Heart Rate Horns Hypertension In Vitro Infarction Ischemia Knowledge Label Lateral Measures Mediating Medulla Oblongata Membrane Potentials Metabotropic Glutamate Receptors Methods Methyltransferase Microinjections Minor Monitor Myocardial Infarction N-Methyl-D-Aspartate Receptors N-Methylaspartate Nerve Neurons Norepinephrine Nucleus solitarius Phenylethanolamine N-Methyltransferase Phenylethyl Alcohol Phosphate Buffer Physiologic pulse Piperazines Play Population Principal Investigator Procedures Propionic Acids Rattus Relative (related person)Research Design Research Personnel Resistance Rhodamine Rhodamines Risk Factors Role Saline Site Slice Spinal Cord Splanchnic Nerves Stroke Sympathetic Nervous System Synapses Synaptic Transmission Techniques Therapeutic Agents Thrombosis Tyrosine 3-Monooxygenase Urethane adrenergic animal data base design dicarboxylate dorsal motor nucleus drug of abuse ethylamine excitatory neuron high risk immunoreactivity in vivo inhibitor/antagonist middle age nisoxetine novel therapeutics postsynaptic pressure presynaptic prevent programs receptor research study response sigma-1 receptor uptake

项目摘要

DESCRIPTION (provided by applicant): With the introduction of high potency "crack" and "freebase", cocaine abuse increased dramatically in the 1980's and 1990's, and is the leading drug of abuse. Epidemiological data have implicated cocaine as a contributing factor to myocardial infarction, stroke, thrombosis, hypertension and arrhythmias in users on the basis of temporal relationship between drug use and event onset. Clinical and animal studies suggest that the central sympathetic nervous system plays a critical role in cocaine-induced cardiovascular abnormality. The hypothesis central to this proposal is that cocaine interacts with sigma-1 receptors located in neurons of the rostral ventrolateral medulla (RVLM), leading to a potentiation of glutamatergic responses, thereby an augmented sympathetic nerve activity in cocaine users. There is evidence that the central action of cocaine is mediated through sigma-1 receptors. The goal of this project is to define the central cardiovascular action of cocaine on RVLM neurons of the rat, with particular reference to sigma-1 receptors. First, immunohisto- chemical studies will examine the expression of sigma-1 receptors and their relationship to subtypes of glutamate receptors in a population of bulbospinally projecting RVLM neurons. Second, the effect of cocaine, which will be microinjected into the RVLM area, on blood pressure, heart rate and greater splanchnic nerve activity will be assessed in urethane-anesthetized rats. In addition, the effect of cocaine on the pressor response will be monitored before and after pretreatment with sigma-1 receptor antagonists or dopamine and norepinephrine uptake inhibitors. Third, intracellular Ca2+ concentrations in dissociated, retrogradely labeled RVLM neurons in response to glutamate and cocaine before and after treatment of sigma-1 receptor antagonists will be measured by means of the Fura 2 method. Fourth, whole-cell patch recordings will be made from retrogradely labeled RVLM neurons in the coronal medullary slice and the effect of cocaine on the electrical activity and synaptic transmission of single neurons will be studied. Collectively, these studies are designed to provide a mechanistic approach to the understanding of the central action of cocaine relative to cardiovascular activity. Cocaine abuse is a risk factor to a variety of cardiovascular disorders. To be able to identify the receptor and transmitters that respond to cocaine will be a major step toward a better understanding of the mechanisms involved in cocaine-induced cardiac disorders. More importantly, the knowledge gained would permit a rational approach to the design of novel therapeutic agents, for example, sigma-1 receptor or subtypes of glutamate receptor antagonists, for the management of cocaine-induced cardiovascular dysfunction.

描述（由申请人提供）：随着高效“快克”和“游离碱”的引入，可卡因滥用在 20 世纪 80 年代和 1990 年代急剧增加，并且是主要的滥用药物。根据吸毒与事件发生之间的时间关系，流行病学数据表明，可卡因是吸毒者心肌梗塞、中风、血栓形成、高血压和心律失常的一个促成因素。临床和动物研究表明，中枢交感神经系统在可卡因引起的心血管异常中发挥着关键作用。该提议的核心假设是，可卡因与延髓头端腹外侧 (RVLM) 神经元中的 sigma-1 受体相互作用，导致谷氨酸能反应增强，从而增强可卡因使用者的交感神经活动。有证据表明可卡因的中枢作用是通过 sigma-1 受体介导的。该项目的目标是确定可卡因对大鼠 RVLM 神经元的中枢心血管作用，特别是 sigma-1 受体。首先，免疫组织化学研究将检查球脊髓突出的 RVLM 神经元群中 sigma-1 受体的表达及其与谷氨酸受体亚型的关系。其次，将在乌拉坦麻醉的大鼠中评估可卡因（将显微注射到 RVLM 区域）对血压、心率和更大内脏神经活动的影响。此外，在用 sigma-1 受体拮抗剂或多巴胺和去甲肾上腺素摄取抑制剂预处理之前和之后，将监测可卡因对升压反应的影响。第三，在 sigma-1 受体拮抗剂治疗之前和之后，将通过 Fura 2 方法测量解离的、逆行标记的 RVLM 神经元对谷氨酸和可卡因的反应的细胞内 Ca2+ 浓度。第四，将从冠状髓质切片中逆行标记的 RVLM 神经元进行全细胞贴片记录，并研究可卡因对单个神经元电活动和突触传递的影响。总的来说，这些研究旨在提供一种机制方法来理解可卡因相对于心血管活动的中心作用。可卡因滥用是多种心血管疾病的危险因素。能够识别对可卡因产生反应的受体和递质将是朝着更好地理解可卡因引起的心脏疾病的机制迈出的重要一步。更重要的是，所获得的知识将允许采用合理的方法来设计新型治疗剂，例如用于治疗可卡因引起的心血管功能障碍的sigma-1受体或谷氨酸受体拮抗剂的亚型。

项目成果

期刊论文数量（58）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endomorphin-like immunoreactivity in the rat dorsal horn and inhibition of substantia gelatinosa neurons in vitro.

大鼠背角的内吗啡样免疫反应性和体外对胶质质神经元的抑制。

DOI：
发表时间：
1999-03
期刊：
影响因子：
3.3
作者：
Wu, S Y;Dun, S L;Wright, M T;Chang, J K;Dun, N J
通讯作者：
Dun, N J

The vasoactive peptide urotensin II stimulates spontaneous release from frog motor nerve terminals.

血管活性肽尾加压素 II 刺激青蛙运动神经末梢自发释放。

DOI：
发表时间：
2003-04
期刊：
影响因子：
0
作者：
Brailoiu, E;Brailoiu, G C;Miyamoto, M D;Dun, N J
通讯作者：
Dun, N J

Cocaine- and amphetamine-regulated transcript peptide and sympatho-adrenal axis.

可卡因和安非他明调节的转录肽和交感肾上腺轴。

DOI：
发表时间：
2006-08
期刊：
影响因子：
0
作者：
Dun, Siok L;Brailoiu, G Cristina;Yang, Jun;Chang, Jaw Kang;Dun, Nae J
通讯作者：
Dun, Nae J

The G protein-coupled receptor GPR30 inhibits proliferation of estrogen receptor-positive breast cancer cells.

G 蛋白偶联受体 GPR30 抑制雌激素受体阳性乳腺癌细胞的增殖。

DOI：
10.1158/0008-5472.can-09-3068
发表时间：
2010-02-01
期刊：
Cancer research
影响因子：
11.2
作者：
Ariazi EA;Brailoiu E;Yerrum S;Shupp HA;Slifker MJ;Cunliffe HE;Black MA;Donato AL;Arterburn JB;Oprea TI;Prossnitz ER;Dun NJ;Jordan VC
通讯作者：
Jordan VC

Hypothalamic orexin A-immunoreactive neurons project to the rat dorsal medulla.

下丘脑食欲素 A 免疫反应性神经元投射到大鼠背髓质。