The present experiments were undertaken to determine: (1) whether bupropion had any direct effects on receptors present in rat brain; (2) whether the drug could down-regulate postsynaptic beta-adrenergic, alpha 2-adrenergic, serotonergic, imipramine and dopaminergic receptors after chronic administration, as had been demonstrated for tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, electroconvulsive therapy (ECT) and "atypical" antidepressants. Bupropion was found to be weak or inactive when its affinity for 14 different receptors present in brain was assessed by binding assays. The drug failed to desensitize beta-adrenergic receptors in the cerebral cortex of the rat as determined by [3H]dihydroalprenolol binding, after being administered at 25 mg/kg (i.p.) once a day for 6 weeks, or after being administered by the intraperitoneal route to rats at doses as large as 150 mg/kg per day for 4 days. When administered at doses of 37.5, 75 and 150 mg/kg per day for 21 days, the drug had no effect on beta-adrenergic, alpha 2-adrenergic, imipramine or serotonergic (5-HT2) receptors in the brain of the rat as determined by Scatchard analysis of the binding data. These data show that the antidepressant activity of bupropion is not associated with a down-regulation of receptors in the CNS commonly implicated in the mechanism of action of antidepressant drugs. Bupropion also produced a dose-dependent tendency to decrease the activity of norepinephrine-stimulated adenylate cyclase in slices of cerebral cortex obtained from rats treated chronically with the drug. However, the decrease was highly variable, was most obvious in tissues obtained from rats receiving large, non-pharmacologically relevant doses (150 mg/kg per day) of the drug and was statistically significant at only one of three concentrations of the agonist that produced maximal stimulation of the enzyme.