title: Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram.
abstract: Rats were chronically treated with the selective serotonin re-uptake inhibitor citalopram [1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril ], by means of osmotic minipumps. Using an infusion concentration of 50 mg/ml citalopram, steady-state plasma concentrations of approximately 0.3 mcM citalopram were maintained for 15 days. Citalopram plasma levels dropped below pharmacologically active concentrations 48 h after removal of the minipumps. Although chronic treatment with citalopram did induce an attenuated response by extracellular levels of 5-hydroxytryptamine (5-HT) after systemic administration of the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), no effect of chronic citalopram treatment was observed when 5-HT(1B) receptor function was evaluated with a local infusion of 5-HT(1B/D) receptor agonist, sumatriptan (3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5methane sulphonamide). Controversially, no augmentation of the increase of 5-HT levels was observed upon systemic administration of citalopram. It is concluded that, although chronic treatment with citalopram does induce desensitisation of 5-HT(1A) receptors, the absence of augmented effects of citalopram on 5-HT levels indicates that other mechanisms compensate for the loss of autoreceptor control.
authors.affiliation: Department of Medicinal Chemistry, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands. t.i.f.h.cremers@farm.rug.nl
authors.forename: T I
authors.initials: TI
authors.lastname: Cremers
authors.forename: E N
authors.initials: EN
authors.lastname: Spoelstra
authors.forename: P
authors.initials: P
authors.lastname: de Boer
authors.forename: F J
authors.initials: FJ
authors.lastname: Bosker
authors.forename: A
authors.initials: A
authors.lastname: Mørk
authors.forename: J A
authors.initials: JA
authors.lastname: den Boer
authors.forename: B H
authors.initials: BH
authors.lastname: Westerink
authors.forename: H V
authors.initials: HV
authors.lastname: Wikström
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects*; D015283:Citalopram / Q000097:blood / Q000493:pharmacokinetics*; D007260:Infusion Pumps; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*; D018170:Sumatriptan / Q000494:pharmacology; D013997:Time Factors
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D017660:Autoreceptors; D015283:Citalopram; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D018170:Sumatriptan