Posted by AndrewB on March 16, 2000, at 12:41:27
In reply to Re: Scott/Amineptine, posted by KarenB on March 16, 2000, at 11:16:26
J Clin Psychiatry 1995 Sep;56(9):395-401
Bupropion: a review of its mechanism of antidepressant activity.
Ascher JA, Cole JO, Colin JN, Feighner JP, Ferris RM, Fibiger HC, Golden RN, Martin P, Potter WZ,
Richelson E, et alDepartment of Neurology/Psychiatry, Burroughs Wellcome Co., Research Triangle Park, N.C., USA.
BACKGROUND: 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. METHOD: 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.
RESULTS: (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. CONCLUSION: 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.
poster:AndrewB
thread:26793
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