Activity of brainstem neurons

脑干神经元的活动

基本信息

批准号：
7257627
负责人：
Nae J Dun
金额：
$ 36.25万
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 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7257627
关键词：
6-Cyano-7-nitroquinoxaline-2,3-dione ACPD Abbreviations Acids Address Adrenergic Agents Adult Affect Aftercare Amines Animal Model Animals Area Arrhythmia BD 1008 BD 1047 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 Elevation Event Excitatory Amino Acid Antagonists Excitatory Postsynaptic Potentials Functional disorder Fura-2 GBR 13069 Glutamate Receptor Glutamates Goals Hanks Balanced Salt Solution Heart Diseases Heart Rate Horns Hypertension In Vitro Infarction Ischemia Knowledge Label Lateral Localized Measures Mediating Medulla Oblongata Membrane Potentials Metabotropic Glutamate Receptors Methods Methyltransferase Microinjections Minor Monitor Myocardial Infarction N-Methyl-D-Aspartate Receptors N-Methylaspartate NE-100 Nerve Neurons Norepinephrine Nucleus solitarius Phenylethanolamine N-Methyltransferase Phenylethyl Alcohol Phosphate Buffer Physiologic pulse Piperazines Play Population Principal Investigator Procedures Propionic acid Pulse taking Purpose Rattus Relative (related person)Research Design Research Personnel Resistance Rhodamine Rhodamines Risk 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 day design dicarboxylate dorsal motor nucleus drug of abuse ethylamine excitatory neuron immunoreactivity in vivo inhibitor/antagonist middle age nisoxetine novel therapeutics piperazine 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）：随着引入高效力“破解”和“ freebase”，可卡因滥用在1980年代和1990年代急剧增加，并且是滥用的主要药物。流行病学数据已将可卡因牵涉到对心肌梗死，中风，血栓形成，高血压和心律不齐的促成因素，这是在药物使用和事件发作之间的时间关系的基础上。临床和动物研究表明，中心交感神经系统在可卡因诱导的心血管异常中起关键作用。该提案的中心假设是可卡因与位于腹侧外侧延髓（RVLM）神经元中的Sigma-1受体相互作用，从而导致谷氨酸能反应的增强，从而增强了可卡因使用者的增强交感神经活性。有证据表明，可卡因的中心作用是通过Sigma-1受体介导的。该项目的目的是定义可卡因对大鼠RVLM神经元的中枢性心血管作用，特别是指Sigma-1受体。首先，免疫史学研究将检查Sigma-1受体的表达及其与谷氨酸受体亚型的关系中，在囊泡纤维投射的RVLM神经元中。其次，可卡因将在RVLM区域进行显微注射，对血压，心率和更大的斑点神经活动的影响，将在氨基甲酸酯 - 麻醉的大鼠中进行评估。另外，可卡因对用Sigma-1受体拮抗剂或多巴胺和去甲肾上腺素摄取抑制剂进行预处理之前和之后，将监测可卡因对压力反应的影响。第三，将通过FURA 2方法测量分离的，逆行标记的RVLM神经元中对谷氨酸和可卡因的逆行标记的RVLM神经元中的细胞内Ca2+浓度。第四个，全细胞贴片记录将由冠状髓质切片中逆行标记的RVLM神经元逆行制成，可卡因对单个神经元的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械方法，以理解可卡因相对于心血管活动的中心作用。可卡因滥用是各种心血管疾病的危险因素。能够识别对可卡因反应的受体和发射器将是更好地理解可卡因诱导的心脏病的机制的主要一步。更重要的是，获得的知识将允许对新型治疗剂的设计进行合理的方法，例如，谷氨酸受体拮抗剂的Sigma-1受体或亚型，用于管理可卡因诱导的心血管功能障碍。