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Analysis for the physiological role of a novel GABAィイD2AィエD2 receptor sub-class.

新型 GABAD2AD2 受体亚类的生理作用分析。

基本信息

批准号：
10670149
负责人：
ONOE Hirotaka
金额：
$ 2.11万
依托单位：
TOKYO METROPOLITAN ORGANIZATION FOR MEDICAL RESEARCH (1999)Tokyo Metropolitan Institute for Neuroscience (1998)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

Previously, we revealed the presence of very high- and high-affinity binding sites (ex. Kd values in the amygdala are ca. 0.4 and 18.7 nM, respectively) in the γ-aminobutyric acid/benzodiazepine (GABAィイD2AィエD2/BZ) receptor in the living monkey brain by an in vivo saturation study using ィイD111ィエD1C-labeled Ro15-4513 with high specific radioactivity (>70 GBq/μmol). To assess the physiological function of the very high-affinity binding sites of GABAィイD2AィエD2/Benzodiazepine (BZ) receptor in the intact living brain, the binding of a ィイD111ィエD1C-labeled BZ partial inverse agonist ([ィイD111ィエD1C]Ro15-4513) of the GABAィイD2AィエD2/BZ receptor was investigated by the positron emission tomography (PET) with conscious and anesthetized monkeys. In the conscious monkey, sleep deprivation or ketamine, a NMDA receptor blocker, treatment increased the binding of [ィイD111ィエD1C]Ro15-4513, but not did that of [ィイD111ィエD1C]Ro15-1788. Furthermore, propofol, a positive allosteric modulator of the GABAィイD2AィエD2/BZ receptors, anesthesia induced decreases in the binding of [ィイD111ィエD1C]Ro15-4513 but not did that of [ィイD111ィエD1C]Ro15-1788. The very high affinity binding sites of [ィイD111ィエD1C]Ro15-4513 were invisible in the most of limbic regions under the propofol anesthesia. These results strongly indicate that the binding characteristics of the [ィイD111ィエD1C]Ro15-4513 in vivo may be related to both the heterogeneity of GABAィイD2AィエD2/BZ receptor and its efficacy modulated by allosteric agents in the living brain.

以前,我们发现的存在非常高,高亲和性结合位点(Kd值在杏仁体内ca。0.4和18.7 nM,分别)在γ氨基丁酸酸/苯二氮(GABAィイD2AィエD2 /商务)受体在大脑活猴子体内的饱和度研究使用ィイD111ィエD1C-labeled ro15 - 4513高的特定的放射性(> 70 GBq /μ摩尔)。评估生理功能的高亲和性结合位点的GABAィイD2AィエD2 /苯二氮(BZ)受体在大脑完整生活的绑定ィイD111ィエD1C-labeled BZ部分反兴奋剂([ィイD111ィエD1C] ro15 - 4513)的GABAィイD2AィエD2 / BZ受体研究了正电子发射断层扫描(PET)与意识和麻醉猴子。在有意识的猴子中，睡眠剥夺或氯胺酮（一种NMDA受体阻滞剂）的治疗增加了Ro15-4513的结合，但没有增加Ro15-1788的结合。此外，丙泊酚是GABA γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。在异丙酚麻醉下，大部分边缘区不可见高亲和力结合位点Ro15-4513。这些结果强烈表明,绑定的特征[ィイD111ィエD1C] ro15 - 4513体内可能与GABA的异质性ィイD2AィエD2 / BZ受体和其功效调制变构代理在大脑生活。