Posted by Darby on October 14, 2000, at 16:58:11
In reply to Wellbutrin: How the hell does this stuff work?, posted by JackD on October 14, 2000, at 0:43:41
Jack:
It's best to do a Medline search at your local college library. Here are a few samples. You're right: bupropion has many actions in the body many of which have yet to be discovered.
Good luck Darby
Dopaminergic mediation of the discriminative
stimulus effects of bupropion in rats
by
Terry P, Katz JL
Psychobiology Section,
NIDA Intramural Research Program,
National Institutes of Health,
Baltimore, MD 21224, USA.
Psychopharmacology (Berl) 1997 Nov; 134(2):201-12Bupropion is a novel, non-tricyclic antidepressant with a primary pharmacological action of monoamine uptake
inhibition. The drug resembles a psychostimulant in terms of its neurochemical and behavioural profiles in vivo, but it
does not reliably produce stimulant-like effects in humans at clinically prescribed doses. Bupropion binds with modest
selectivity to the dopamine transporter, but its behavioural effects have often been attributed to its inhibition of
norepinephrine uptake. This experiment examines monoaminergic involvement in the discriminative stimulus effects of
bupropion. Rats were trained to press one lever when injected i.p. with bupropion (17.0 mg/kg), and another lever
when injected with saline. In substitution tests, dose-response curves were obtained for several monoamine uptake
inhibitors. Nine of ten dopamine uptake blockers fully substituted for bupropion; the exception, indatraline (LU
19-005), partially substituted (71% bupropion-appropriate responding). Serotonin and norepinephrine uptake
blockers (zimelidine and nisoxetine, respectively) produced negligible or limited substitution, and the anti-muscarinic
dopamine uptake blocker benztropine produced limited partial substitution. A series of dopamine D1-like and D2-like
receptor agonists were also tested: only the D2-like agonist RU 24213 fully substituted; three other D2-like agonists
and four D1-like agonists partially substituted (50% < drug responding < 80%). Antagonism of the discriminative
effects of bupropion was obtained with a D1- and a D2-like dopamine antagonist. The results demonstrate strong
similarities with those obtained using other dopamine uptake inhibitors as training drugs, and support the view that
the behavioural effects of bupropion are primarily mediated by dopaminergic mechanisms.
Antidepressant profile of bupropion
and three metabolites in mice
by
Martin P, Massol J, Colin JN, Lacomblez L, Puech AJ
Departement de Pharmacologie,
Faculte de Medicine Pite-Salpetriere, Paris,
Pharmacopsychiatry 1990 Jul; 23(4):187-94Bupropion is a novel antidepressant, distinct from tricyclic antidepressants both neurochemically and behaviorally.
Bupropion forms several metabolites in both rodents and humans. Three chemically different molecules - BW 306, BW
494, and BW 287 - were selected. Comparative assessment of antidepressant activity of bupropion and its
metabolites in mice, and pharmacological analysis of possible mechanisms of action of the parent drug and its
metabolites (using interaction studies with pimozide, D,L-propranolol, and prazosin) were carried out. The results
obtained show that: bupropion has a pharmacological spectrum in various animal models which predicts both
antidepressant and stimulatory activity in man. BW 306 is the most active of the metabolites studied and, compared
to bupropion, seems more "antidepressant" and less stimulant. BW 494, compared to bupropion or BW 306, has a
lower degree of activity in various tests used to evaluate antidepressants. BW 287 has no effect in any of the tests
used in this study. The interaction studies with pimozide, D,L-propranolol, and prazosin in the various tests have
shown that: the stimulatory effect of bupropion, BW 306, and BW 494 is antagonized by both pimozide and prazosin.
in the behavioral despair test, the reduction in the duration of immobility by bupropion and BW 494 is antagonized by
pimozide, but not by prazosin or D,L-propranolol. the antagonism of reserpine-induced hypothermia by bupropion and
BW 306 is significantly decreased by prazosin and D,L-propranolol, but not by pimozide. These data suggest that the
clinical antidepressant profile (without a major stimulatory effect) observed in man after administration of bupropion is
related to metabolite BW 306 and possibly to BW 494, rather than to bupropion itself.
Bupropion: a review of its mechanism of antidepressant activity.
J Clin Psychiatry 1995 Sep;56(9):395-401 (ISSN: 0160-6689)Ascher JA; Cole JO; Colin JN; Feighner JP; Ferris RM; Fibiger HC; Golden RN; Martin P; Potter WZ; Richelson E; et al [Find other articles with
these Authors]
Department 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.Bupropion in depression. II. The role of metabolites in clinical outcome.
Arch Gen Psychiatry 1988 Feb;45(2):145-9 (ISSN: 0003-990X)Golden RN; De Vane CL; Laizure SC; Rudorfer MV; Sherer MA; Potter WZ [Find other articles with these Authors]
Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, MD.We studied the steady-state pharmacokinetics of bupropion hydrochloride, a unicyclic aminoketone antidepressant, in depressed patients.
The metabolites hydroxybupropion (HB), threohydrobupropion, and erythrohydrobupropion predominated over the parent compound in
plasma and cerebrospinal fluid at steady state. Plasma concentrations of each metabolite correlated with cerebrospinal fluid concentrations.
Higher plasma metabolite concentrations were associated with poor clinical outcome. This relationship was most striking with HB; plasma
HB levels were greater than 1250 ng/mL in all five nonresponders and less than 1200 ng/mL in all seven responders. Plasma HB levels
correlated with postreatment plasma homovanillic acid levels. High levels of bupropion metabolites may be associated with poor clinical
outcome due to toxic effects involving dopaminergic systems. Alternatively, a curvilinear dose-response relationship may exist for
bupropion metabolites. Future studies should explore the clinical utility of plasma metabolite measurements in enhancing the efficacy of
treatment with bupropion.
Down regulation of beta-receptors by bupropion and its major metabolite in mouse brain.
Neuropharmacology 1986 Dec;25(12):1323-6 (ISSN: 0028-3908)Perumal AS; Smith TM; Suckow RF; Cooper TB
Mice were treated with bupropion Compound II (major metabolite of bupropion) or desmethylimpramine (DMI) twice a day
intraperitoneally for either 1 or 3 weeks. The binding of dihydroalprenolol and spiroperidol in the frontal cortex and limbic forebrain areas
were analyzed. There was a significant reduction in beta-receptors in the frontal cortex induced by DMI at both times examined.
Bupropion showed a significant reduction of beta-receptor in the frontal cortex by 3 weeks. Though propiophenone did not have any
significant effect on beta-receptors in the frontal cortex, it down-regulated beta-receptors in the limbic forebrain area significantly by 1 and
3 weeks. There was no significant effect of buropion or propiophenone on the binding of spiroperidol either in the cortex (S2 receptor) or
in the limbic forebrain (dopaminergic). These results show that bupropion may exert part of its clinical effect through its metabolite
propiophenone.
Evidence that the acute behavioral and electrophysiological effects of bupropion (Wellbutrin) are mediated by a noradrenergic mechanism.
Neuropsychopharmacology 1994 Oct;11(2):133-41 (ISSN: 0893-133X)Cooper BR; Wang CM; Cox RF; Norton R; Shea V; Ferris RM [Find other articles with these Authors]
Division of Pharmacology Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.Bupropion (BW 323U66) has been considered a dopaminergic antidepressant based on its ability to inhibit the uptake of dopamine (DA)
somewhat more selectively than it inhibits uptake of norepinephrine (NE) or serotonin (5-HT). This report describes new evidence that
bupropion selectively inhibits firing rates of NE cells in the locus coeruleus (LC) at doses significantly lower than those that inhibit activity
of midbrain DA cells or dorsal raphe 5-HT cells. The IC50 dose (13 mg/kg i.p.) for inhibition of LC firing produced plasma concentrations
that were not significantly different from those generated by the ED50 in the Porsolt test (10 mg/kg i.p.). The fourfold higher dose needed
to inhibit DA cell firing (IC50 = 42 mg/kg i.p.) was similar to the dose associated with locomotor stimulation in freely moving rats.
Bupropion did not change the firing rates of 5-HT cells in the dorsal raphe nucleus at any dose. In both in vitro and in vivo tests, the
metabolite 306U73 (hydroxybupropion), a weak inhibitor of NE uptake, was approximately equipotent to bupropion with regard to
inhibition of LC cells. Another metabolite, 494U73, had no effect on LC firing rates over a wide range of doses. Because of species
variation in metabolism, 306U73 was not detected in plasma of rats after i.v. doses of bupropion that inhibited LC firing. Only trace
amounts of 306U73 were detected after bupropion dosing for the Porsolt test. Pretreatment with reserpine markedly depleted
catecholamines and reduced (by 30-fold) the potency of bupropion to inhibit LC firing.(ABSTRACT TRUNCATED AT 250 WORDS).
Effect of plasma from patients containing bupropion and its metabolites on the uptake of norepinephrine.
Neuropharmacology 1986 Feb;25(2):199-202 (ISSN: 0028-3908)Perumal AS; Smith TM; Suckow RF; Cooper TB [Find other articles with these Authors]
The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the presence of buffer and plasma from
patients containing bupropion and its metabolites. Even though bupropion and its metabolite (compound II) were equipotent in
inhibiting the uptake of NE in buffer, compound II was twice as active as bupropion in the presence of human plasma. When the inhibition
of uptake of NE in the presence of plasma, obtained from patients on bupropion on steady-state, was correlated with levels of bupropion
and its metabolites (II, III, IV) a highly significant correlation was seen in the presence of compound II. Since this compound accumulated
in plasma from patients 20-100 times that of the parent compound, the mode of action of bupropion may in part be due to the effect of
this compound on the uptake of NE.
poster:Darby
thread:46309
URL: http://www.dr-bob.org/babble/20001012/msgs/46350.html