Investigation of the SSRI augmentation properties of 5-HT(2) receptor antagonists using in vivo microdialysis.
Recent evidence that 5-HT(2) receptors exert a negative influence on central 5-hydroxytryptamine (5-HT) neurones suggests that 5-HT(2) receptor antagonists may augment the effects of serotonin selective reuptake inhibitors (SSRIs). The present study investigated whether pre-treatment with 5-HT(2) receptor antagonists enhances the effect of SSRI administration on hippocampal extracellular 5-HT of freely moving rats. Administration of the SSRI citalopram at a low (2mg kg(-1)) and higher (4 mg kg(-1)) dose, increased dialysate 5-HT by 5- and 8-fold, respectively. Pre-treatment with the 5-HT(2) receptor antagonist ketanserin (4 mg kg(-1)) augmented the effect of 4 mg kg(-1) but not 2mg kg(-1) citalopram. The effect of 4 mg kg(-1) citalopram was also augmented by pre-treatment with either the 5-HT(2C) receptor antagonist SB 242084 (0.5mg kg(-1)) or the 5-HT(2A) receptor antagonist MDL 100907 (0.5mg kg(-1)). As with citalopram, fluoxetine elevated dialysate 5-HT at both a low (5mg kg(-1)) and higher (20mg kg(-1)) dose. However, neither dose of fluoxetine was augmented by ketanserin (4 mg kg(-1)). These results confirm recent findings that 5-HT(2) receptor antagonists augment the effect of citalopram on extracellular 5-HT, and indicate the involvement of 5-HT(2C) and possibly 5-HT(2A) receptors. The lack of augmentation of fluoxetine might reflect the intrinsic 5-HT(2) receptor antagonist properties of this drug.
Boothman
Laura J
LJ
University Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, UK. laura.boothman@pharm.ox.ac.uk
Mitchell
Stephen N
SN
Sharp
Trevor
T
D000704:Analysis of Variance; D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014851:Wakefulness / Q000187:drug effects
D012701:Serotonin; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors