Mignot E, Renaud A, Nishino S, Arrigoni J, Guilleminault C, Dement W C
Stanford University, School of Medicine, Sleep Disorder Center, Palo Alto, CA 94304.
Psychopharmacology (Berl). 1993;113(1):76-82. doi: 10.1007/BF02244337.
Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.
发作性睡病目前通过使用抗抑郁药来控制与快速眼动（REM）相关的症状，如猝倒，以及使用类安非他明兴奋剂来治疗嗜睡。兴奋剂和抗抑郁药均通过突触前增强单胺能传递来发挥作用，但这两类化合物均缺乏药理学特异性。为了确定哪种单胺选择性地参与了这些化合物的治疗作用，我们使用人类疾病的犬类模型研究了选择性单胺摄取抑制剂和释放增强剂对猝倒的影响。总共测试了14种作用于肾上腺素能（地昔帕明、尼索西汀、去甲替林、托莫西汀、维洛沙嗪）、5-羟色胺能（芬氟拉明、氟西汀、吲达品、帕罗西汀、齐美利定）和多巴胺能（安非利酸、胺苯环庚烯、安非他酮、GBR 12909）系统的化合物。该研究还纳入了一些临床上有趣但药理学选择性较低的其他化合物，即可卡因、右旋苯丙胺、哌醋甲酯、诺米芬辛和匹莫林。所有影响去甲肾上腺素能传递的化合物在所有测试犬中均以低剂量完全抑制了犬类猝倒，而主要改变5-羟色胺能和多巴胺能传递的化合物在高剂量时要么无活性，要么部分有活性。我们的结果表明，肾上腺素能系统在猝倒控制以及可能的REM睡眠性肌张力缺失中起优先作用。我们的研究结果还表明，犬类发作性睡病是评估抗抑郁药药理学特异性的有用工具。
