Récepteurs 5-HT1B de la sérotonine et effets antidépresseurs des inhibiteurs de recapture sélectifs de la sérotonine

Abstract

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT_1B 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.) increased extracellular serotonin levels 〚5-HT〛_ext in the ventral hippocampus 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 the 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5-HT_1B receptor or its blockade with the mixed 5-HT_1B/1D receptor antagonist, GR 127935, potentiates the effect of a single administration of paroxetine 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-HT_1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT_1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT_1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT_1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs.