5-HT depletion, but not 5-HT1A antagonist, prevents the anxiolytic-like effect of citalopram in rat contextual conditioned fear stress model

Objective: Selective serotonin reuptake inhibitors (SSRIs) have been widely used in the treatment of most anxiety disorders. In this study, to clarify the mechanism of the anxiolytic effect, we investigated the mechanism underlying the effect of the SSRI citalopram on rat contextual conditioned fear stress (CFS), an animal model of anxiety. Methods: Rats individually received footshocks in a shock chamber. More than 1 day later, they were given citalopram and/or DL-p-chlorophenylalanine (PCPA), various subtype-selective serotonin (5-HT) receptor antagonists: the 5-HT1A receptor antagonist WAY 100635, the 5-HT2A receptor antagonist MDL 100907, the 5-HT2C receptor antagonist SB 242084, the 5-HT3 receptor antagonist tropisetron, the 5-HT4 receptor antagonist GR 125487, the 5-HT6 receptor antagonist SB 258585 or the 5-HT7 receptor antagonist SB 269970. After drug administration, freezing behaviour, which was used as an index of anxiety, was analysed in the same shock chamber without shocks. Results: Citalopram dose dependently reduced conditioned freezing behaviour. The anxiolytic-like effect of citalopram was prevented completely by pretreatment with the 5-HT-depleting agent PCPA, but not by the 5-HT1A receptor antagonist WAY 100635. Furthermore, none of the subtype-selective 5-HT receptor antagonists significantly affected conditioned freezing or affected the anxiolytic-like effect of citalopram. Conclusion: The anxiolytic-like effect of citalopram in contextual CFS model depends on 5-HT availability. In addition, contextual CFS model is suggested to be completely different from conventional anxiety models in neural mechanism or manners of serotonergic involvement. However, further studies are needed to identify the pharmacological mechanisms responsible for the anxiolytic-like effect of citalopram.