Blockade of serotonin 5-HT1B and 5-HT2A receptors suppresses the induction of locomotor activity by 5-HT reuptake inhibitors,citalopram and fluvoxamine,in NMRI mice exposed to a novel environment: a comparison to other 5-HT receptor subtypes

Rationale Though 5-HT plays an important role in the modulation of motor function, which is perturbed in depressive states, little is known concerning the influence of serotonin reuptake inhibitors (SSRIs) on locomotor activity (LA). Recently, we demonstrated that SSRIs, such as citalopram, enhance LA in mice exposed to a novel environment. Objectives This study examined the role of multiple classes of 5-HT receptor in citalopram-induced LA. Methods The most selective antagonists currently available were used. Results Citalopram-induced LA was dose-dependently attenuated by the 5-HT_1B/1D receptor antagonists, S18127, GR125,743 and GR127,935, and by the selective 5-HT_1B antagonist, SB224,289, but unaffected by the selective 5-HT_1A antagonist, WAY100,635. The selective antagonists at 5-HT_2A receptors, MDL100,907 and SR46,349 also dose-dependently attenuated induction of locomotion by citalopram, whereas the 5-HT_2B antagonist, SB204,741, and the 5-HT_2B/2C antagonist, SB206,553 were ineffective. Further, the selective 5-HT_2C antagonist, SB242,084, potentiated the response to citalopram. Selective antagonists at 5-HT₃ (ondansetron), 5-HT₄ (GR125,487), 5-HT₆ (SB271,046) and 5-HT₇ (SB269,970) receptors did not significantly modify the action of citalopram. Underpinning these findings, SB224,289, GR125,743, MDL100,907 and SR46,349 likewise attenuated induction of locomotion by a further SSRI, fluvoxamine. Conclusions The locomotor response to SSRIs of mice exposed to a novel environment is mediated via 5-HT_1B and 5-HT_2A receptors. In view of the importance of motor function to the etiology and treatment of depression, the significance of these observations to the clinical actions of SSRIs will be of interest to elucidate.