Investigation of the SSRI augmentation properties of 5-HT sub(2) receptor antagonists using in vivo microdialysis

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