Relevance of dorsal raphe nucleus firing in serotonin 5-HT2C receptor blockade-induced augmentation of SSRIs effects

Selective serotonin reuptake inhibitors are the most widely prescribed antidepressant drugs. However, they exhibit a slow onset of action, putatively due to the initial decrease in serotonin cell firing mediated via somato-dendritic autoreceptors. Interestingly, blockade of 5-HT2C receptors significantly potentiates the effect of citalopram, a selective serotonin reuptake inhibitor, on serotonin efflux in the hippocampus and prefrontal cortex (Cremers, T.I.F.H., Giorgetti, M., Bosker, F.J., Hogg, S., Arnt, J., Mork, A., Honig, G., Bøgesø, K.P., Westerink, B.H.C., den Boer, J.A., Wikstrøm, H.V., Tecott, L.H., 2004. Inactivation of 5-HT2C receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29, 1782–1789; Cremers, T.I.F.H., Rea, K., Bosker, F.J., Wikström, H.V., Hogg, S., Mørk, A., Westerink, B.H.C., 2007. Augmentation of SSRI effects on serotonin by 5-HT2C antagonists: mechanistic studies. Neuropsychopharmacology 32, 1550–1557.). Using in vivo electrophysiology, we show in the present study that the purported selective 5-HT2C receptor antagonist, SB242,084, dose-dependently counteracts citalopram-induced inhibition of serotonin cell firing. Even though the effect of SB242,084 is significant at a dose found in vivo to also partially occupy 5-HT2A receptors, indicating a possible contribution of a partial blockade of 5-HT2A receptors together with 5-HT2C receptors, we suggest that high occupancy at 5-HT2C receptors is essential for the blockade of the inhibitory effect of citalopram on 5-HT cell firing. Using microdialysis, we also show that the potentiation by SB242,084 on serotonin efflux requires an action of citalopram outside the terminal, most likely at the somato-dendritic level (i.e., on serotonin cell firing). Further experiments using local 5-HT2C receptor blockade indicate a role of 5-HT2C receptors located in the prefrontal cortex. Modulation of short or long feedback loops originating in the prefrontal cortex by 5-HT2C receptors could directly inhibit serotonin efflux, or alternatively, regulate serotonin cell firing in the dorsal raphe nucleus, thereby modulating serotonin efflux indirectly.