Mechanism of ethanol-clonidine synergistic sedation

乙醇-可乐定协同镇静作用机制

• 批准号: 7028305
• 负责人: TARA S BENDER
• 金额: $ 2.77万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7028305
• 关键词: alpha adrenergic receptor; biological signal transduction; brain electrical activity; clonidine; drug interactions; electrochemistry; electroencephalography; ethanol; immunocytochemistry; laboratory rat; locus coeruleus; mitogen activated protein kinase; neuromuscular system; nitric oxide; nitric oxide synthase; phosphorylation; predoctoral investigator; psychomotor function; sensory depression

DESCRIPTION (provided by applicant): Ethanol-induced motor in coordination is synergistically enhanced by clonidine, a centrally acting antihypertensive drug (alpha-2 agonist). Reported findings suggest a role for alpha-2 adrenergic receptor signaling in ethanol-induced motor incoordination. However, a molecular mechanism for the synergistic interaction between ethanol and alpha-2 receptors has not yet been determined. This study will test the hypothesis that ethanol and clonidine act through different pathways to synergistically increase nitric oxide (NO) levels in the locus ceruleus (LC) to produce the synergistic deficit in motor coordination. It is further hypothesized that clonidine, acting at the alpha-2A receptor, enhances the effects of ethanol through a phosphorylation cascade involving p42/44 MARK, which activates nNOS. These hypotheses will be tested by undertaking behavioral (rotorod), immunohistochemical (cFos/cJun), and in vivo electrochemical (NO measurements in the LC) studies. The use of pharmacological (agonists/antagonists) and genetic (antisense) interventions will help identify key molecular players. This project will provide valuable information about the molecular mechanism of a clinically relevant drug interaction and about ethanol-induced motor in coordination.

描述（由申请人提供）：可乐定是一种中枢作用的降压药（α -2激动剂），可协同增强乙醇诱导的协调运动。报告的研究结果表明，α -2肾上腺素能受体信号在乙醇诱导的运动不协调中起作用。然而，乙醇和α -2受体之间协同作用的分子机制尚未确定。本研究将验证乙醇和可乐定通过不同途径协同增加蓝核座（LC）一氧化氮（NO）水平，从而产生运动协调性协同缺陷的假设。进一步的假设是，可乐定作用于α - 2a受体，通过磷酸化级联作用增强乙醇的作用，涉及p42/44 MARK，激活nNOS。这些假设将通过进行行为学（rotorod）、免疫组织化学（cFos/cJun）和体内电化学（LC中的NO测量）研究来验证。使用药理学（激动剂/拮抗剂）和遗传（反义）干预将有助于确定关键的分子参与者。该项目将为临床相关药物相互作用的分子机制和乙醇诱导的运动协调提供有价值的信息。