Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT1B autoreceptors

Rationale: 5-HT autoreceptors regulate extracellular 5-HT levels and have been suggested to limit the effects of acute treatment with selective serotonin reuptake inhibitors (SSRI). Objectives: The role of terminal 5-HT1B autoreceptors was assessed by comparing the effects of a SSRI on extracellular 5-HT in wildtype and 5-HT1B receptor knockout mice, and by using a 5-HT1B receptor antagonist. Since systemic SSRI-administration also activates somatodendritic 5-HT1A autoreceptors, a SSRI was administered locally to study the role of terminal 5HT1B autoreceptors. Methods: In vivo microdialysis in wildtype and 5-HT1B receptor knockout (KO) mice was used to study the effects of the 5-HT1B receptor agonist CP93129 (1 μM), the SSRI fluvoxamine (0.3 and 1.0 μM) and the 5-HT1B receptor antagonist NAS-181 (1 μM) on extracellular 5-HT in the medial prefrontal cortex (PFC). Results: The 5-HT increase induced by local SSRI-administration was augmented in 5-HT1B KO mice as compared to wildtype mice and was augmented by simultaneous administration of a 5-HT1B receptor antagonist in the