Ascher J A, Cole J O, Colin J N, Feighner J P, Ferris R M, Fibiger H C, Golden R N, Martin P, Potter W Z, Richelson E
Department of Neurology/Psychiatry, Burroughs Wellcome Co., Research Triangle Park, N.C., USA.
J Clin Psychiatry. 1995 Sep;56(9):395-401.
The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study. A review of the relevant biochemical, in vivo brain microdialysis, electrophysiologic, behavioral, and clinical data clarifies what is known about this unique compound and suggests possible modes of action.
A panel of 11 experts was convened for a conference to discuss bupropion's mechanism of antidepressant activity. Four of the panelists presented current research findings, followed by a discussion.
(1) Biochemical studies suggest down-regulation of postsynaptic beta-adrenoceptors and desensitization of the norepinephrine-stimulated adenylate cyclase in the rat cortex occur only after chronic administration of very high doses of bupropion. (2) In vivo brain microdialysis studies demonstrate that, after chronic administration, there is an enhancement of bupropion-induced increases in extracellular dopamine in the nucleus accumbens. (3) Electrophysiologic data show that with acute dosing, bupropion reduces the firing rates of noradrenergic neurons in the locus ceruleus. The firing rates of dopaminergic neurons are reduced by bupropion in the A9 and A10 areas of the brain, but only at very high doses, and bupropion does not alter the firing rates of serotonergic neurons in the dorsal raphe. (4) Behavioral studies show that the most active metabolite of bupropion, hydroxybupropion (306U73), appears to be responsible for a large part of the compound's effects in animal models of antidepressant activity. (5) Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders.
The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated.
经过多年研究，新型抗抑郁药安非他酮的作用机制仍不明确。回顾相关的生化、体内脑微透析、电生理、行为学及临床数据，有助于明确关于这种独特化合物的已知信息，并提示其可能的作用方式。
召集了由11名专家组成的小组召开会议，讨论安非他酮的抗抑郁活性机制。4名小组成员介绍了当前的研究结果，随后进行了讨论。
（1）生化研究表明，仅在长期给予非常高剂量的安非他酮后，大鼠皮层中突触后β-肾上腺素能受体的下调以及去甲肾上腺素刺激的腺苷酸环化酶的脱敏才会出现。（2）体内脑微透析研究表明，长期给药后，安非他酮诱导的伏隔核细胞外多巴胺增加有所增强。（3）电生理数据显示，急性给药时，安非他酮可降低蓝斑中去甲肾上腺素能神经元的放电频率。在脑的A9和A10区域，安非他酮可降低多巴胺能神经元的放电频率，但仅在非常高的剂量下才会出现，且安非他酮不会改变中缝背核中5-羟色胺能神经元的放电频率。（4）行为学研究表明，安非他酮最具活性的代谢产物羟基安非他酮（306U73）似乎在抗抑郁活性动物模型中对该化合物的大部分作用负责。（5）临床研究表明，安非他酮可增强去甲肾上腺素能功能活性，这可通过褪黑素羟基代谢产物排泄增加来反映，同时去甲肾上腺素周转率可能出现代偿性下降。在一项研究中，安非他酮使无反应者的多巴胺代谢产物高香草酸血浆水平升高，但反应者中未出现这种情况。
安非他酮的作用机制似乎存在一种不寻常的、尚未完全理解的去甲肾上腺素能联系。安非他酮代谢产物羟基安非他酮可能在安非他酮的抗抑郁活性中起关键作用，其抗抑郁活性似乎主要与长期的去甲肾上腺素能效应相关。安非他酮轻度的中枢神经系统激活作用似乎归因于较弱的多巴胺能机制。有一些证据表明多巴胺可能有助于安非他酮的抗抑郁特性。安非他酮的抗抑郁作用不是由5-羟色胺能介导的。
