Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT1B autoreceptors:: a microdialysis study in knockout mice

Rationale: Serotonin (5-HT) autoreceptors regulate extracellular 5-HT levels and have been suggested to limit the effects of acute treatment with selective serotonin reuptake inhibitors (SSRIs). Objectives: The role of terminal 5-HT1B autoreceptors was assessed by comparing the effects of a SSRI on extracellular 5-HT in wild-type and 5-HT1B receptor knockout (KO) mice and by using a 5-HT1B receptor antagonist. Since systemic SSRI administration also activates somatodendritic 5HT(1A) autoreceptors, a SSRI was administered locally to study the role of terminal 5-HT1B autoreceptors. Methods: In vivo microdialysis in wild-type and 5-HT1B receptor KO mice was used to study the effects of the 5HT(1B) receptor agonist CP93129 (1 muM), the SSRI fluvoxamine (0.3 muM and 1.0 muM) and the 5-HT113 receptor antagonist NAS-181 (1 muM) on extracellular 5-HT in the medial prefrontal cortex. Results: The 5-HT increase induced by local SSRI administration was augmented in 5-HT1B KO mice relative to wild-type mice and was augmented by simultaneous administration of a 5-HT1B receptor antagonist in the latter genotype. Basal 5-HT levels did not differ between the two genotypes. Activation of 5-HT1B receptors by CP93129 decreased extracellular 5-HT, whereas 5-HT levels in wild-type mice were not affected by the 5-HT1B receptor antagonist NAS-181. In 5-HT1B KO mice, NAS-181 did not affect extracellular 5-HT and did not further increase the effect of fluvoxamine, showing that NAS-181 is a selective 5-HT1B receptor antagonist. The greater increase in 5-HT levels following combined administration of a SSRI with NAS-181 in wild-type mice, relative to 5-HT1B KO mice, suggests possible adaptive changes in the KO mice. Conclusions: The present study shows that terminal 5-HT1B autoreceptors play a significant role in the regulation of 5-HT release in the prefrontal cortex.