Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro
Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro
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DOI：
10.1124/jpet.106.106583
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发表时间：
2006-11-01
影响因子：
3.5
通讯作者：
Fischman, Alan J.
中科院分区：
文献类型：
--
作者：
Madras, Bertha K.;Xie, Zhihua;Fischman, Alan J.
2-[（二苯基甲基）亚磺酰基]乙酰胺（莫达非尼），主要用于治疗发作性睡病，正在接受其他神经精神疾病和医疗条件的评估。莫达非尼的神经化学底物尚未解决。我们假设莫达非尼通过调节多巴胺（DAT）、去甲肾上腺素（NET）或血清素（SERT）转运蛋白活性来增强觉醒。在体内，我们通过正电子发射断层扫描成像确定了莫达非尼对DAT和NET的占有率;在体外，我们确定了莫达非尼对DAT、NET、SERT和恒河猴痕量胺受体1（TA 1）的活性。在恒河猴中，通过[C-11]2 β-甲氧羰基-3 β-4-（氟苯基）托烷检测纹状体DAT的莫达非尼占位，通过[C-11]（S，S）-2-（α-（2-甲氧基苯氧基）苄基）吗啉检测丘脑NET的莫达非尼占位。在体外，莫达非尼在DAT-人胚肾（HEK），NET-HEK，和SERT-HEK细胞中的作用进行了研究单独或与TA 1受体的组合。莫达非尼（i. v.）占据纹状体DAT位点（5 mg/kg：35 +/-12%，n = 4; 8 mg/kg：54 +/-3%，n = 3）。在丘脑中，莫达非尼占据NET位点（5 mg/kg：16 +/-7.8%，n = 6; 8 mg/ kg：44 +/- 12%; n = 2）。在体外，莫达非尼抑制[H-3]多巴胺（IC 50 = 6.4 μ M）、[H-3]去甲肾上腺素（IC 50 = 35.6 μ M）和[H-3] 5-羟色胺（IC 50> 500 μ M）通过人DAT、NET和SERT的转运。莫达非尼不激活TA 1-HEK细胞中的TA 1受体，但它增强了TA 1-DAT和TA 1-NET细胞中苯乙胺激活TA 1的单胺转运蛋白依赖性增强，但在TA 1-SERT细胞中没有。目前的数据提供了令人信服的证据表明，莫达非尼占据的DAT和NET在生活的恒河猴脑，并提出了莫达非尼影响觉醒的可能性，通过与脑中的儿茶酚胺转运蛋白相互作用。
2-[(Diphenylmethyl) sulfinyl]acetamide (modafinil), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by positron emission tomography imaging; in vitro, we determined modafinil activity at the DAT, NET, SERT, and rhesus monkey trace amine receptor 1 (TA1). In rhesus monkey, modafinil occupancy of striatal DAT was detected by [C-11]2 beta-carbomethoxy-3 beta-4-(fluorophenyl) tropane and of thalamic NET by [C-11](S,S)-2-(alpha-(2-methoxyphenoxy)benzyl) morpholine. In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor. Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12%, n = 4; 8 mg/kg: 54 +/- 3%, n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.8%, n = 6; 8 mg/ kg: 44 +/- 12%; n = 2). In vitro, modafinil inhibited [H-3] dopamine (IC50 = 6.4 mu M), [H-3] norepinephrine (IC50 = 35.6 mu M), and [H-3] serotonin (IC50 > 500 mu M) transport via the human DAT, NET, and SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but it augmented a monoamine transporter-dependent enhancement of phenethylamine activation of TA1 in TA1-DAT and TA1-NET cells, but not in TA1-SERT cells. The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.