Cooper B R, Hester T J, Maxwell R A
J Pharmacol Exp Ther. 1980 Oct;215(1):127-34.
Bupropion (BW 323U; Wellbutrin), a novel compound with antidepressant effects in man, was found to reduce immobility in an "experimental helplessness" forced swimming antidepressant test in rats as did imipramine and amitriptyline. Higher doses produced elevated locomotor activity in an automated open field and produced stereotyped sniffing which was contrasted with apomorphine. When bupropion or desmethylimipramine was given before intracisternal injections of 6-hydroxydopamine, bupropion produced a dose-related selective antagonism of the destruction of dopamine neurons, while under the same conditions, desmethylimipramine produced a dose-related selective antagonism of the destruction of noradrenergic neurons. Studies in which the dose of bupropion and the dose of 6-hydroxydopamine were varied revealed that a dose-related selective antagonism of dopamine depletion by 6-hydroxydopamine occurred when doses up to and including 50 mg/kg i.p. to bupropion were administered. Some antagonism of norepinephrine depletion also occurred at 100 mg/kg of bupropion i.p. Bupropion also selectively reversed the dopamine depletion produced by alpha-methyl-m-tyrosine, a finding which is consistent with the view that bupropion is a dopamine uptake inhibitor in vivo. The importance of dopamine systems for the behavioral effects of bupropion were also studied. When the locomotor stimulant effects of bupropion were tested in rats with chronic destruction of dopamine neurons produced by 6-hydroxydopamine, bupropion failed to elevate locomotor activity. Rats treated with procedures using 6-hydroxydopamine to produce relatively selective norepinephrine depletions responded to bupropion with locomotor activity stimulation like controls. Rats with similar depletions of either dopamine or norepinephrine were also tested for the ability of low doses of bupropion to reduce immobility in the "experimental helplessness" forced swim antidepressant test. Prior destruction of dopamine neurons prevented activity of bupropion in this test. Results indicate that bupropion is a selective dopamine uptake inhibitor in vivo and that dopaminergic systems play an important role in its central nervous system pharmacology.
安非他酮（BW 323U；安非他酮）是一种对人类具有抗抑郁作用的新型化合物，研究发现它在大鼠的“实验性无助”强迫游泳抗抑郁试验中能减少不动时间，作用与丙咪嗪和阿米替林类似。更高剂量的安非他酮在自动旷场试验中会增加运动活性，并产生刻板嗅探行为，这与阿扑吗啡的作用形成对比。当在脑池内注射6-羟基多巴胺之前给予安非他酮或去甲丙咪嗪时，安非他酮会产生与剂量相关的对多巴胺能神经元破坏的选择性拮抗作用，而在相同条件下，去甲丙咪嗪会产生与剂量相关的对去甲肾上腺素能神经元破坏的选择性拮抗作用。对安非他酮剂量和6-羟基多巴胺剂量进行变化的研究表明，当腹腔注射高达50mg/kg（包括50mg/kg）的安非他酮时，会出现与剂量相关的对6-羟基多巴胺所致多巴胺耗竭的选择性拮抗作用。腹腔注射100mg/kg的安非他酮时，对去甲肾上腺素耗竭也有一定的拮抗作用。安非他酮还能选择性地逆转α-甲基-m-酪氨酸所致的多巴胺耗竭，这一发现与安非他酮在体内是多巴胺摄取抑制剂的观点一致。还研究了多巴胺系统对安非他酮行为效应的重要性。当在由6-羟基多巴胺导致多巴胺能神经元慢性破坏的大鼠中测试安非他酮的运动兴奋作用时，安非他酮未能增加运动活性。用6-羟基多巴胺进行相对选择性去甲肾上腺素耗竭处理的大鼠，对安非他酮的反应是运动活性受到刺激，与对照组相似。还对多巴胺或去甲肾上腺素耗竭程度相似的大鼠进行了低剂量安非他酮在“实验性无助”强迫游泳抗抑郁试验中减少不动时间能力的测试。预先破坏多巴胺能神经元会阻止安非他酮在此试验中的活性。结果表明，安非他酮在体内是一种选择性多巴胺摄取抑制剂，多巴胺能系统在其中枢神经系统药理学中起重要作用。
