5-HT1B autoreceptors limit the effects of selective serotonin re-uptake inhibitors in mouse hippocampus and frontal cortex

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 1B receptor subt ype in mediating the effects of selective serotonin re-uptake inhibitors (S SRIs). Using in vivo intracerebral microdialysis in awake mice, we show tha t a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) incre ased extracellular serotonin levels [5-HT](ext) in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hi ppocampus, 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, but not at 5 mg/kg. In addition, either the absence of the 5-HT1B r eceptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 12 7935, potentiated the effect of a single administration of paroxetine on ex tracellular 5-HT levels more in the Ventral hippocampus than in the frontal cortex. These data suggest that 5-HT1B autoreceptors limit the effects of SSRIs on dialysate 5-HT levels at serotonergic nerve terminals.