Kanbayashi T, Honda K, Kodama T, Mignot E, Nishino S
Sleep Research Center, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
Neuroscience. 2000;99(4):651-9. doi: 10.1016/s0306-4522(00)00239-6.
Using a canine model of narcolepsy and selective DA and NE uptake inhibitors, we have recently shown that DA uptake inhibition promotes wakefulness, while NE uptake inhibition inhibits rapid eye movement sleep and cataplexy. In order to further delineate the respective roles of the dopaminergic and noradrenergic systems in the pharmacological control of symptoms of narcolepsy, we compared the potency of amphetamine isomers (D- and L-amphetamines) and a derivative (L-methamphetamine) on wakefulness and cataplexy. Their respective effects on these narcolepsy symptoms were then compared with their in vivo effects on extracellular DA levels in the caudate and NE levels in the frontal cortex during local drug perfusion in narcoleptic dogs. Polygraphic recordings demonstrated that D-amphetamine was about twice as potent as L-amphetamine, and was six times more potent than L-methamphetamine in increasing wakefulness and reducing slow-wave sleep. D-Amphetamine and L-amphetamine were equipotent in reducing rapid eye movement sleep and cataplexy, and L-methamphetamine was about half as potent as L- and D-amphetamines. D-Amphetamine was found to be more potent in increasing DA efflux than L-amphetamine, and L-methamphetamine was found to have little effect on DA efflux; there was no significant difference in the potencies of the three derivatives on NE efflux. The potencies of these amphetamines on wakefulness correlated well with DA, but not NE, efflux in the brain of narcoleptic dogs during local drug perfusion. Our current results further exemplify the importance of the DA system for the pharmacological control of electroencephalogram arousal and suggest that increased DA transmission mediates the wake-promoting effects of amphetamine-like stimulants.
利用发作性睡病犬模型以及选择性多巴胺（DA）和去甲肾上腺素（NE）摄取抑制剂，我们最近发现，抑制DA摄取可促进清醒，而抑制NE摄取则会抑制快速眼动睡眠和猝倒。为了进一步阐明多巴胺能系统和去甲肾上腺素能系统在发作性睡病症状药物控制中的各自作用，我们比较了苯丙胺异构体（D - 和L - 苯丙胺）及其衍生物（L - 甲基苯丙胺）对清醒和猝倒的作用强度。然后，将它们对这些发作性睡病症状的各自影响，与在发作性睡病犬局部药物灌注期间，它们对尾状核细胞外DA水平和额叶皮质NE水平的体内影响进行比较。多导睡眠图记录表明，在增加清醒和减少慢波睡眠方面，D - 苯丙胺的效力约为L - 苯丙胺的两倍，比L - 甲基苯丙胺强六倍。D - 苯丙胺和L - 苯丙胺在减少快速眼动睡眠和猝倒方面效力相当，而L - 甲基苯丙胺的效力约为L - 和D - 苯丙胺的一半。发现D - 苯丙胺在增加DA外流方面比L - 苯丙胺更有效，而L - 甲基苯丙胺对DA外流几乎没有影响；这三种衍生物对NE外流的效力没有显著差异。在局部药物灌注期间，这些苯丙胺对清醒的效力与发作性睡病犬大脑中的DA外流密切相关，但与NE外流无关。我们目前的结果进一步证明了DA系统在脑电图觉醒药物控制中的重要性，并表明增加DA传递介导了苯丙胺样兴奋剂的促醒作用。
