Gozlan H, Laporte A M, Thibault S, Schechter L E, Bolaños F, Hamon M
INSERM U 288, Neurobiologie Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
Neuropharmacology. 1994 Mar-Apr;33(3-4):423-31. doi: 10.1016/0028-3908(94)90072-8.
The effects of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an alkylating agent producing irreversible blockade of various membrane bound receptors in brain, were investigated on four different types of serotonin receptors, 5-HT1A, 5-HT1B, 5-HT2A and 5-HT3, in various brain regions in the rat. In addition, the fate of central benzodiazepine- and "R"-zacopride-specific binding sites was also examined in rats treated with EEDQ. Membrane binding assays and/or quantitative autoradiography with appropriate radioligands indicated that EEDQ inactivated 5-HT1A, 5-HT1B and 5-HT2A sites, but was poorly active on 5-HT3, benzodiazepine and "R" sites. Among the receptors affected by EEDQ, hippocampal 5-HT1A sites were the most sensitive to the alkylating agent (ID50 approximately 1 mg/kg i.p.), followed by the cortical 5-HT2A (ID50 approximately 3 mg/kg i.p.) and the striatal 5-HT1B (ID50 approximately 6 mg/kg i.p.) sites. Pretreatment by selective ligands partially protected hippocampal 5-HT1A sites from irreversible inactivation by EEDQ (10 mg/kg i.p.) with the following order of efficacy: WAY 100635 > spiperone > BMY 7378 > ipsapirone. Similarly, pretreatment by spiperone (5 mg/kg i.p.) also reduced the ability of EEDQ to inactivated cortical 5-HT2A receptors. Analyses of the time-course recovery of respective binding sites after EEDQ administration showed that the turnover rate of 5-HT1A sites did not significantly differ in the dorsal raphe nucleus and in various forebrain areas (hippocampus, septum, cerebral cortex; half-life: approximately 4 days), but was lower than that of cortical 5-HT2A sites (half-life: 2.9 days).
研究了N-乙氧羰基-2-乙氧基-1,2-二氢喹啉（EEDQ），一种能对大脑中各种膜结合受体产生不可逆阻断作用的烷基化剂，对大鼠不同脑区中四种不同类型的5-羟色胺受体（5-HT1A、5-HT1B、5-HT2A和5-HT3）的影响。此外，还检测了用EEDQ处理的大鼠中枢苯二氮䓬和“R”-扎考必利特异性结合位点的变化情况。用合适的放射性配体进行的膜结合试验和/或定量放射自显影表明，EEDQ使5-HT1A、5-HT1B和5-HT2A位点失活，但对5-HT3、苯二氮䓬和“R”位点的活性较弱。在受EEDQ影响的受体中，海马体中的5-HT1A位点对这种烷基化剂最为敏感（腹腔注射半数失活剂量约为1 mg/kg），其次是皮质中的5-HT2A位点（腹腔注射半数失活剂量约为3 mg/kg）和纹状体中的HT1B位点（腹腔注射半数失活剂量约为6 mg/kg）。用选择性配体进行预处理可部分保护海马体中的5-HT1A位点不被EEDQ（腹腔注射10 mg/kg）不可逆失活，其效力顺序如下：WAY 100635 > 螺哌隆 > BMY 7378 > 伊沙匹隆。同样，用螺哌隆（腹腔注射5 mg/kg）进行预处理也降低了EEDQ使皮质中5-HT2A受体失活的能力。对EEDQ给药后各结合位点的时间进程恢复情况进行分析表明，5-HT1A位点在中缝背核和各个前脑区域（海马体、隔区、大脑皮质；半衰期：约4天）的周转率没有显著差异，但低于皮质中HT2A位点的周转率（半衰期：2.9天）。
