Investigation of the SSRI augmentation properties of 5-HT2 receptor antagonists using in vivo microdialysis

Recent evidence that 5-HT2 receptors exert a negative influence on central 5-hydroxytryptamine (5-HT) neurones suggests that 5-HT, receptor antagonists may augment the effects of serotonin selective reuptake inhibitors (SSRIs). The present study investigated whether pretreatment with 5-HT, 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 (2 mg kg(-1)) and higher (4 mg kg(-1)) dose, increased dialysate 5-HT by 5- and 8-fold, respectively. Pre-treatment with the 5-HT2 receptor antagonist ketanserin (4 mg kg(-1)) augmented the effect of 4 mg kg(-1) but not 2 mg kg(-1) citalopram. The effect of 4 mg kg(-1) citalopram was also augmented by pre-treatment with either the 5-HT2C receptor antagonist SB 242084 (0.5 mg kg (-1)) or the 5-HT2A receptor antagonist MDL 100907 (0.5 mg kg(-1)). As with citalopram, fluoxetine elevated dialysate 5-HT at both a low (5 mg kg (-1)) and higher (20 mg kg(-1)) dose. However, neither dose of fluoxetine was augmented by ketanserin (4 mg kg(-1)). These results confirm recent findings that 5-HT2, receptor antagonists augment the effect of citalopram on extracellular 5-HT, and indicate the involvement of 5-HT2C and possibly 5-HT2A receptors. The lack of augmentation of fluoxetine might reflect the intrinsic 5-HT2 receptor antagonist properties of this drug. (c) 2005 Elsevier Ltd. All rights reserved.