Evidence that the Acute Behavioral and Electrophysiological Effects of Bupropion (Wellbutrin®) Are Mediated by a Noradrenergic Mechanism

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Abstract
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 IP) 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 IP). The fourfold higher dose needed to inhibit DA cell firing (IC50 = 42 mg/kg IP) 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 (hydroxy-bupropion), 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 IV 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. The effects of clonidine, a direct acting α2 agonist, were not significantly changed by reserpine. Likewise, a reduction in the effect of bupropion on LC firing was observed in vitro after depletion of catecholamines with reserpine or tetrabenazine. These results suggest that bupropion preferentially affects NE neurons in locus coeruleus at doses that are active in animal antidepressant tests. The doses of bupropion required to inhibit DA cell firing were associated with inhibition of DA uptake and behavioral stimulation and were significantly higher than those selectively producing behavioral effects in animal antidepressant tests. The acute electrophysiological actions of bupropion on NE cells require a reserpine-sensitive store of NE and occur at doses having activity in antidepressant screening tests.

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