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

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 - D2A - D2/BZ) receptor in the livingmonkey brain by an in vivo saturation study using D111 -labeled Ro15-4513 with high specificradioactivity (> 70gbq /μmol). To assess the physiological function of the very high-affinity bindingsites of GABA - D2/Benzodiazepine (BZ) receptor in the intact living brain，the binding of a i D111 -labeled BZ partial inverse agonist ([i D111 - D1C]Ro15-4513) of theGABA - D2A - D2/BZ receptor was investigated by the positron emission tomography (PET) with consciousand anesthetized monkeys. In the conscious monkey, sleep deprivation or ketamine，a NMDA receptor blocker, treatment increased the binding of [D111 - D1C]Ro15-4513，but not did that of [D111 - D1C]Ro15-1788. Furthermore, propofol，a positive allosteric modulator of the GABA D2A D2/BZ receptors，anesthesia induced decreases in the binding of [D111 - D1C]Ro15-4513 but not did that of[i - 111 D1C]Ro15-1788. The very high affinity binding sites of [i - 111 D1C]Ro15-4513 wereinvisible in the most of limbic regions under the propofol anesthesia. These results stronglyindicate that the binding characteristics of the [D111 - D1C]Ro15-4513 in体内may be related toboth the heterogeneity of GABA D2A - D2/BZ receptor and its efficacy modulated by allosteric agentsin the living brain。

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.