Subchronic treatment of rats with the potential antidepressant tiflucarbine down-regulated the noradrenaline (NA) responses of the cAMP system in cerebral cortex. A concomitant 25% decrease in dihydroalprenolol binding sites in cerebral cortical membranes was observed. The effect was dose-dependent (ED50 = 6 mg/kg), required a 9 days' treatment period, and was reversible 5 days after discontinuation of treatment. Tiflucarbine treatment increased the specific activity of soluble calmodulin (CaM)-dependent phosphodiesterase in rat brain. Tiflucarbine bound to CaM and inhibited its interaction with the phosphodiesterase. Adrenergic denervation by 6-hydroxydopamine (6-OHDA) injection prevented both the beta-adrenoceptor down-regulation and the increase in specific activity of the phosphodiesterase. We suggest that a synergistic interaction between a presynaptic phosphodiesterase inhibition and the NA reuptake blockade was responsible for the down-regulation induced by tiflucarbine. The data are compatible with the reported antidepressant properties of this drug.