5-MT1B receptors mediate the antidepressant effects of selective serotoninreuptake inhibitors.

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) in creased extracellular serotonin levels [5-HT](ext) in the ventral hippocamp us and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT](ext) in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at th e 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5 -HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist , GR 127935, potentiates the effect of a single administration of paroxetin e on [5-HT](ext) more in the ventral hippocampus than in the frontal cortex . Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B rece ptors mediate the antidepressant-like effects of SSRIs. Taken together thes e data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presyn aptic 5-HT1B heteroreceptors are likely to be required for the antidepressa nt activity of SSRIs. (C) 2001 Academie des sciences/Editions scientifiques et medicales Elsevier SAS.