Some neurochemical properties of a new antidepressant, bupropion hydrochloride (Wellbutrin™)

Bupropion is a novel antidepressant agent. In the present study, an attempt was made to gain some insight into the mechanism of the drug's antidepressant activity. In vitro studies revealed that bupropion was a weak, competitive inhibitor of norepinephrine (NE) uptake into rat hypothalamic synaptosomes and of dopamine (DM) uptake into rat striatal synaptosomes, having IC50 values of 6.5 ± 0.6 × 10−6 M and 3.4 ± 0.4 × 10−6 M, respectively. At 1 × 10−5 M, the drug produced a 20 ± 3% inhibition of serotonin (5-HT) uptake into rat hypothalamic synaptosomes. The drug was also a weak inhibitor of the ATP-Mg+2 stimulated uptake of NE and DM into synaptic vesicles of whole rat brain, having IC50 values of 3.3 × 10−5 M and 6.0 × 10−5 M, respectively. Bupropion had no dose-dependent effect on the spontaneous release of NE, DM, and 5-HT from these synaptosomal preparations in concentrations as high as 1 × 10−4 M. Brain monoamine oxidase (MAO) activity in vitro was not affected by concentrations of the drug ranging from 10−7 M to 10−5 M. Bupropion was also without effect on brain MAO, 1 hr after i.p. doses in rats as high as 100 mg/kg. The ED50 value for bupropion necessary to inhibit the uptake of 3H-catecholamines by 50% into synaptosomes incubated in the serum from rats treated with the drug was 40 mg/kg i.p., while its ED50 value for antidepressant activity, as judged by the ability of bupropion to reverse the immobile posture of “helpless” rats, was 8 mg/kg i.p. These neurochemical properties of bupropion on uptake of biogenic amines and on MAO activity serve to distinguish it from other antidepressant drugs of the tricyclic and MAO inhibitor classes.