ONTOGENY OF GABA A RECEPTOR COMPLEX MEASURED WITH PET

用 PET 测量 GABA 受体复合体的个体发育

• 批准号: 6294950
• 负责人: OTTO MUZIK
• 金额: $ 25.88万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-21 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6294950
• 关键词: GABA receptor; adolescence (12-20); adult human (21+); age difference; anticonvulsants; benzodiazepines; bioimaging /biomedical imaging; carbon; developmental neurobiology; drug interactions; gender difference; inhibitor /antagonist; intelligence; magnetic resonance imaging; middle childhood (6-11); neuropharmacology; partial seizure; pediatric pharmacology; positron emission tomography; preschool child (1-5); radionuclides; receptor binding; receptor expression; young adult human (21-34)

DESCRIPTION: (Adapted from the applicant's Description) The overall aim of this application is to determine in vivo age-related changes of the GABAA receptor complex in children. A knowledge of GABAA receptor ontogeny is relevant in understanding the efficacy of pharmacological agents which bind to the GABAA receptor complex, as well as agents which alter brain GABA concentration. Changes in whole brain distribution of the GABAA receptor complex in vivo will be measured in children with epilepsy by applying positron emission tomography (PET) using the tracer [C-11]flumazenil (FMZ), a benzodiazepine antagonist which binds to the alpha subunit of the GABAA receptor complex. The studies are designed to extract normative data from FMZ PET studies being performed on epileptic children under evaluation for surgical treatment, since ethical guidelines prohibit the study of normal children with PET. Specific Aim 1 will determine the changes in brain values for FMZ volume of distribution (VD) with age in children with partial (focal) epilepsy. Specific Aim 2 will determine the effects of vigabatrin, an anticonvulsant which increases brain GABA levels, on values for FMZ VD with age in children with partial epilepsy. Specific Aim 3 will determine differences in the regional pattern of FMZ VD in the hemisphere contralateral to the epileptic focus in children with partial epilepsy as compared to normal adults. The hypotheses to be tested will increase our understanding of the ontogeny of the human GABA alpha receptor complex. In addition, these experiments will improve our understanding of how changes in GABA alpha receptors with age might affect the pharmacology of anitconvulsants, as well as the pharmacology of other therapeutic drugs and drugs of abuse acting at this receptor complex. Our studies will facilitate the application of PET studies of GABA alpha receptors in other pediatric patient groups, such as adolescents with alcohol abuse. For example, should we confirm our preliminary finding that the regional pattern of FMZ VD in children over 6 years of age does not differ from that in adults, this would facilitate the use of adult control subjects for analysis of regional differences of GABA alpha receptors in various pediatric disorders using statistical parametric mapping (SPM).

描述：（根据申请人的描述进行了改编）的总体目的 该应用是为了确定GABAA体内与年龄相关的变化 儿童的受体复合物。 GABAA受体个体发育的知识是 与了解结合的药理学剂的功效相关 GABAA受体复合物以及改变脑GABA的药物 专注。 GABAA受体的全脑分布的变化 复杂的体内将在患有癫痫的儿童中测量 使用示踪剂[C-11]氟马兹尼（FMZ），A的正电子发射断层扫描（PET），A 苯二氮卓类拮抗剂与GABAA的α亚基结合 受体复合物。 研究旨在从FMZ提取规范数据 对癫痫儿童进行的宠物研究正在评估 手术治疗，因为道德准则禁止研究正常 宠物的孩子。 具体目标1将确定大脑价值的变化 对于FMZ分布量（VD），患有部分（焦点）的儿童年龄 癫痫。 具体目标2将确定vigabatrin的影响， 抗惊厥药会增加大脑GABA水平，以FMZ VD的值 患有部分癫痫的儿童的年龄。 具体目标3将决定 半球FMZ VD区域模式的差异 与正常人相比 成年人。 要测试的假设将增加我们对人GABAα受体复合物的个体发育的理解。 此外，这些实验将提高我们对随着年龄的增长的GABAα受体的变化的理解，可能会影响AnitConconvul​​sant的药理学，以及其他治疗药物和在这种受体复合物中作用的滥用药物的药理学。 我们的研究将促进GABAα受体在其他儿科患者组中的PET研究，例如酗酒的青少年。 例如，如果我们确认我们的初步发现，即6岁以上儿童中FMZ VD的区域模式与成年人没有差异，这将有助于使用成人控制受试者分析使用统计参数映射（SPM）的各种儿科疾病中GABA Alpha受体的区域差异。