Seconds-resolved in vivo measurements reveal rapid, serotonin transporter-independent plasma serotonin clearance

Serotonin potently regulates vascular tone, permeability, and platelet activation. Because of this, circulating plasma-free serotonin is normally maintained at very low concentrations through rapid, serotonin transporter (SERT)-mediated uptake into platelets. The well-established tolerability of SERT-blocking selective serotonin reuptake inhibitors (SSRIs), however, suggests that additional systemic mechanisms preserve serotonin homeostasis when SERT is inhibited. To test the hypothesized existence of such non-SERT plasma serotonin clearance, here we used an electrochemical biosensor to measure, with 8-second resolution, the dynamics of plasma serotonin in the presence and absence of pharmacologic SERT inhibition both in vivo in the rat jugular vein and ex vivo in fresh, whole blood. In vivo, we found that, following IV serotonin challenges in animals with intact platelet function, plasma serotonin concentrations rapidly (t_1/2 ∼2 minutes) fell below the sensor's detection limit, ∼20nM in vivo. In contrast, after using the SSRI escitalopram to inhibit SERT, we observed a large, transient (ie, >8-14 minutes) elevation of baseline plasma serotonin, and subsequent challenges with exogenous serotonin exhibited a notably larger peak and a slower (t_1/2 ∼10 minutes) return to baseline. Ex vivo experiments performed using fresh, whole blood indicated that the level of SSRI employed in our studies is sufficient to effectively abolish platelet SERT activity, suggesting that the postescitalopram clearance of supraphysiological serotonin concentrations in intact animals occurs via yet-to-be-identified, SERT-independent clearance pathways occurring in the solid tissues. By revealing a SERT-independent compensatory clearance capacity that reduces plasma serotonin levels when platelet uptake is impaired, these findings refine current models of the platelet-mediated regulation of plasma serotonin.