Effects of serotoninergic agents on downregulation of beta-adrenoceptors by the selective serotonin reuptake inhibitor sertraline.
The results of the present study show that the down-regulation of beta-adrenoceptors of rat brain, induced by subacute administration of sertraline, is facilitated when this selective serotonin reuptake inhibitor was co-administered with the serotonin releaser, norfenfluramine, or the serotonin terminal autoreceptor antagonist, methiothepin. The respective drug combination produced a reduction in Bmax of [3H]dihydroalprenolol binding to cortical membranes of treated rats at a dose of the releaser, release enhancer, or sertraline, which was ineffective when administered alone. In a similar manner, the 5-HT1A agonists, gepirone and 8-OH-DPAT, were found to facilitate the downregulation of beta-adrenoceptors induced by sertraline. The 5-HT1B agonist, 3-trifluoromethylphenylpiperazine, and the 5-HT2 antagonist, ritanserin, showed neither facilitation nor antagonism of sertraline, but the 5-HT3 antagonist, ondansetron, attenuated the decrease of Bmax of [3H]dihydroalprenolol binding elicited by sertraline. Agents that putatively increase the serotoninergic activity facilitated the down-regulation of beta-adrenoceptors induced by sertraline, suggesting that the enhancement of serotonin transmission, expected of the selective serotonin reuptake inhibitor itself, may play a role in this effect of sertraline. Whether the downregulation of brain beta-adrenoceptors by sertraline plays any role in its antidepressant activity cannot be deduced from these experiments.
Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
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D015057:1-Naphthylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D004082:Dihydroalprenolol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004347:Drug Interactions; D004357:Drug Synergism; D008297:Male; D008719:Methiothepin / Q000008:administration & dosage / Q000494:pharmacology; D009642:Norfenfluramine / Q000008:administration & dosage / Q000494:pharmacology; D017294:Ondansetron / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D016713:Ritanserin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D020280:Sertraline
D015057:1-Naphthylamine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D004082:Dihydroalprenolol; D008719:Methiothepin; D009642:Norfenfluramine; D017294:Ondansetron; D010879:Piperazines; D011743:Pyrimidines; D011943:Receptors, Adrenergic, beta; D016713:Ritanserin; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline; C018406:1-(3-trifluoromethylphenyl)piperazine; C039979:gepirone