Mechanism of ethanol-clonidine synergistic sedation

描述(由申请人提供)：中枢作用的抗高血压药物(α-2激动剂)可乐定协同增强乙醇诱导的运动协调。报道的研究结果表明，α-2肾上腺素能受体信号在乙醇诱导的运动不协调中发挥了作用。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斑(LC)一氧化氮(NO)水平以产生运动协调的协同缺陷的假说。进一步假设，可乐定作用于α-2A受体，通过p42/44Mark的磷酸化级联反应增强乙醇的作用，激活nNOS。这些假说将通过进行行为学(Rotorod)、免疫组织化学(CFos/cJun)和体内电化学(LC中没有测量)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。该项目将提供有关临床相关药物相互作用的分子机制和乙醇诱导的协调马达的有价值的信息。

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.