Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram.
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.
Cremers
T I
TI
Department of Medicinal Chemistry, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands. t.i.f.h.cremers@farm.rug.nl
Spoelstra
E N
EN
de Boer
P
P
Bosker
F J
FJ
Mørk
A
A
den Boer
J A
JA
Westerink
B H
BH
Wikström
H V
HV
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
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