REGULATING CEREBROSPINAL FLUID FORMATION

调节脑脊液形成

• 批准号: 2266303
• 负责人: BARRY J. HOFFER
• 金额: $ 14.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2266303
• 关键词: adenylate cyclase; anesthetics; antipsychotic agents; autoradiography; brain circulation; cerebral hemorrhage; cerebrospinal fluid; choroid plexus; dopamine receptor; drug receptors; ganglions; intracranial pressure; isotope dilution method; laboratory rat; neuropharmacology; serotonin receptor; trauma

Improved medical means of reducing CSF production would be of major benefit to patients with increased intracranial pressure (ICP). Such patients include those with acute head trauma, intracranial hemorrhage, some tumors, and malfunctioning CSF shunts. Trauma is the fourth leading cause of death, and up to 70% of these deaths are due to the head injury. Fatal head injury is associated with increased ICP, usually within the first 3-5 days. Drugs capable of reducing ICP, by reducing CSF production, might save some of these lives. The goal of this project is to develop further our understanding of the neural control of the production of cerebrospinal fluid (CSF) by the choroid plexus. It is currently known that sympathetic tone inhibits secretion of CSF. Preliminary data from our laboratory suggest that neuroleptics, or antipsychotic drugs, also cause a decrease in the net production of CSF. It is hypothesized that he receptors responsible for mediating this effect are localized to the choroid plexus and/or the sympathetic ganglia. We will study both of the receptors labeled by 3H-SCH-23390 and 3H-mesulergine. One of these is the 5-HT1c receptor, but it is not yet clear what subtype of receptor the second one is. Many drugs have high affinity for both receptors. Pharmacological characterization of the latter receptor will be carried out using receptor and second messenger assays. The major effort will be to study modulation of CSF production by agonists and antagonists at these receptors. Rats will be treated acutely with which the cisterna magna is cannulated will be compared with the isotope dilution method. Rats treated with superior cervical ganglionectomy will be studied to determine whether some drugs act by modulating sympathetic tone. To determine the chronic efficacy of drugs which decrease CSF production, rats will be treated with such drugs via implanted minipumps and tested to determine whether tolerance has developed to an acute administration of the drug. Evidence of crosstolerance to CSF- modulating effects will be sought in rats treated chronically with neuroleptics and challenged acutely with another agent, such as a glucocorticoid. To evaluate the possibility that drugs which reduce CSF production act by reducing blood flow to the choroid plexus, the 14C- iodoantipyrine technique will be used to measure regional blood flow both before and after drug administration. It is planned that promising animal studies will be followed up by clinical study proposals.

减少脑脊液产生的改进医疗手段将带来重大益处 颅内压（ICP）增高的患者。 此类患者 包括急性头部外伤、颅内出血、某些肿瘤、 和脑脊液分流器故障。 创伤是第四大原因 死亡，其中高达 70% 的死亡是由于头部受伤造成的。 致命的 头部受伤与 ICP 升高有关，通常在前 3-5 天内 天。 能够通过减少脑脊液产生来降低 ICP 的药物可能 拯救其中一些生命。 该项目的目标是进一步发展 我们对脑脊液产生的神经控制的理解 脉络丛的液体（CSF）。 目前已知，同情 音调抑制脑脊液的分泌。 我们实验室的初步数据 表明抗精神病药或抗精神病药物也会导致 CSF 的净产量。 据推测，他的受体 负责介导这种效应的区域位于脉络丛 和/或交感神经节。 我们将研究这两种受体 由 3H-SCH-23390 和 3H-美舒麦角标记。 其中之一是 5-HT1c 受体，但尚不清楚第二个受体是什么亚型 是。 许多药物对这两种受体都具有高亲和力。 药理作用 后一种受体的表征将使用受体进行 和第二信使测定。 主要努力将是研究调制 这些受体的激动剂和拮抗剂对脑脊液产生的影响。 老鼠 将接受小脑延髓池插管的急性治疗 与同位素稀释法相比。 用上等药物治疗的大鼠 将研究颈神经节切除术以确定某些药物是否起作用 通过调节交感神经张力。 确定药物的长期疗效 减少脑脊液产生，大鼠将通过以下方式接受此类药物治疗： 植入微型泵并进行测试以确定是否已产生耐受性 急性给药。 CSF 交叉耐受的证据- 将在长期治疗的大鼠中寻找调节作用 抗精神病药并用另一种药物（例如 糖皮质激素。 评估减少脑脊液的药物的可能性 通过减少脉络丛的血流量来产生 14C- 碘安替比林技术将用于测量局部血流量 给药前和给药后。 计划有前途的动物 研究之后将提出临床研究建议。