Augmentation with a 5-HT(1A), but not a 5-HT(1B) receptor antagonist critically depends on the dose of citalopram.
Pharmacokinetic and pharmacodynamic parameters of the selective serotonin reuptake inhibitor 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-5-phtalancarbonitril (citalopram) were determined in order to find optimal conditions for augmentation of its effect on extracellular serotonin [5-hydroxytryptamine (5-HT)] through blockade of 5-HT(1A) and 5-HT(1B) autoreceptors. Citalopram dose-dependently (0.3-10 micromol/kg s.c.) increased serotonin levels in ventral hippocampus of conscious rats. At plasma levels above approximately 0.15 microM, the effect of citalopram on extracellular 5-HT was augmented by both a 5-HT(1A) [N-[2-[4-(2-mehoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridil) cyclohexa necarboxamide trihydrochloride (Way 100635), 1 micromol/kg s.c.] and a 5-HT(1B) receptor antagonist (2'-methyl-4'-(5-methyl-[1,2, 4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy]-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935), 1 micromol/kg s.c.). However, at plasma levels of the selective serotonin reuptake inhibitor below 0.15 microM, the effects of the antagonists diverged viz. the 5-HT(1B) receptor antagonist was still able to potentiate citalopram's effect on extracellular 5-HT, while the 5-HT(1A) receptor antagonist was no longer effective. These results suggest that in contrast to 5-HT(1B) autoreceptors, indirect activation of 5-HT(1A) autoreceptors by citalopram is critically related to the dose of selective serotonin reuptake inhibitor administered. The latter may have consequences for selective serotonin reuptake inhibitor augmentation strategies with 5-HT(1A) receptor antagonists in the therapy of depression and anxiety disorders.
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
de Boer
P
P
Liao
Y
Y
Bosker
F J
FJ
den Boer
J A
JA
Westerink
B H
BH
Wikström
H V
HV
D000818:Animals; D017660:Autoreceptors / Q000187:drug effects; D015283:Citalopram / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology*; D013997:Time Factors
D017660:Autoreceptors; D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; D015283:Citalopram; C090701:GR 127935; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide