A role for midbrain raphe gamma aminobutyric acid neurons in 5-hydroxytryptamine feedback control.

New data show that 5-hydroxytryptamine (5-HT) neurons of the dorsal raphe nucleus (DRN) are subject to feedback control from 5-HT2 receptors, but the circuitry involved is uncertain. This study investigated whether 5-HT2 receptor agonism activates DRN gamma-aminobutyric acid (GABA) neurons, which are known to inhibit neighbouring 5-HT neurons. Systemic administration of the 5-HT2 receptor agonist, DOI, caused a striking increase in Fos-immunoreactivity in the DRN. This effect was abolished by the 5-HT2 antagonists ritanserin and MDL 100907, but not SB 206553, indicating the involvement of 5-HT2A receptors. Importantly, DOI-induced Fos-immunoreactivity in the DRN was extensively colocalized in GAD67-immunoreactive neurons. These findings suggest that activated local GABA neurons may play an important role in 5-HT2 receptor-mediated feedback control of DRN 5-HT neurons

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