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  • Title: Augmentation with a 5-HT(1A), but not a 5-HT(1B) receptor antagonist critically depends on the dose of citalopram.
    Author: Cremers TI, de Boer P, Liao Y, Bosker FJ, den Boer JA, Westerink BH, Wikström HV.
    Journal: Eur J Pharmacol; 2000 May 26; 397(1):63-74. PubMed ID: 10844100.
    Abstract:
    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.
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