The potential antidepressant tiflucarbine down-regulates beta-adrenoceptors in rat brain.
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.
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013569:Synapses / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D000928:Antidepressive Agents; D007211:Indoles; D011943:Receptors, Adrenergic, beta; D013876:Thiophenes; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; C050288:tiflucarbine; D009638:Norepinephrine