Activity of brainstem neurons

脑干神经元的活动

• 批准号: 7409132
• 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
• 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/7409132
• 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

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90年代急剧增加，并且是主要的滥用药物。流行病学数据表明，根据吸毒与事件发生之间的时间关系，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起关键作用。该建议的核心假设是可卡因与位于延髓头端腹外侧（RVLM）神经元中的σ-1受体相互作用，导致交感神经反应增强，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。本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，特别是对sigma-1受体的作用。首先，免疫组织化学研究将检查sigma-1受体的表达及其与延髓脊髓投射RVLM神经元群体中谷氨酸受体亚型的关系。其次，将在麻醉大鼠中评估可卡因对血压、心率和更大内脏神经活动的影响，可卡因将被微量注射到RVLM区域。此外，在用σ-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，将通过Fura 2方法测量在σ-1受体拮抗剂处理之前和之后响应于谷氨酸和可卡因的解离的、逆行标记的RVLM神经元中的细胞内Ca 2+浓度。第四，将从逆行标记的RVLM神经元的冠状延髓切片和可卡因的电活动和突触传递的单个神经元的影响进行全细胞补丁记录将被研究。总的来说，这些研究的目的是提供一个机制的方法来理解可卡因相对于心血管活动的中枢作用。可卡因滥用是多种心血管疾病的危险因素。能够识别对可卡因有反应的受体和递质将是更好地理解可卡因引起的心脏疾病机制的重要一步。更重要的是，所获得的知识将允许合理的方法来设计新的治疗剂，例如，sigma-1受体或谷氨酸受体拮抗剂的亚型，用于管理可卡因诱导的心血管功能障碍。