5‐HT1B Receptor‐Mediated Regulation of Serotonin Clearance in Rat Hippocampus In Vivo

: The 5‐hydroxytryptamine (5‐HT; serotonin) transporter (5‐HTT) is important in terminating serotonergic neurotransmission and is a primary target for many psychotherapeutic drugs. Study of the regulation of 5‐HTT activity is therefore important in understanding the control of serotonergic neurotransmission. Using high‐speed chronoamperometry, we have demonstrated that local application of 5‐HT1B antagonists into the CA3 region of the hippocampus prolongs the clearance of 5‐HT from extracellular fluid (ECF). In the present study, we demonstrate that the 5‐HT1B antagonist cyanopindolol does not produce this effect by increasing release of endogenous 5‐HT or by directly binding to the 5‐HTT. Dose‐response studies showed that the potency of cyanopindolol to inhibit clearance of 5‐HT was equivalent to that of the selective 5‐HT reuptake inhibitor fluvoxamine. Local application of the 5‐HT1A antagonist WAY 100635 did not alter 5‐HT clearance, suggesting that the effect of cyanopindolol to prolong clearance is not via a mechanism involving 5‐HT1A receptors. Finally, the effect of low doses of cyanopindolol and fluvoxamine to inhibit clearance of 5‐HT from ECF was additive. These data are consistent with the hypothesis that activation of terminal 5‐HT1B autoreceptors increases 5‐HTT activity.