Serotonin ClearanceIn VivoIs Altered to a Greater Extent by Antidepressant-Induced Downregulation of the Serotonin Transporter than by Acute Blockade of this Transporter

Abstract

Serotonin uptake, mediated by the serotonin transporter (SERT), is blocked acutely by antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), but such blockade does not correlate temporally with the onset of therapeutic improvement. Treatment with SSRIs for 21 d induced downregulation of the SERT (Benmansour et al., 1999). The time course of SERT downregulation as well as the time course for its recovery after cessation of treatment with the SSRI sertraline were investigated using tritiated cyanoimipramine to measure SERT binding sites. To determine if there was a temporal correlation between the time when sertraline induced downregulation of the SERT and when marked alteration in SERT function occurred, clearance of locally applied 5-HT into the CA3 region of hippocampus was achieved using in vivo electrochemistry. After 4 or 10 d treatment with sertraline, SERT binding sites decreased very little (15-30%), and the chronoamperometric signals for serotonin in sertraline-treated rats were comparable with ones obtained in control animals. By contrast, after 15 d of treatment, when SERT binding sites were markedly reduced by 80%, there was robust decrease in the clearance of 5-HT. Moreover, the functional consequences of SERT downregulation as measured by chronoamperometry were significantly greater than those seen after acute blockade of the SERT by SSRIs. SERT binding sites decreases are not a consequence of reduced SERT gene expression, as revealed by in situ hybridization measurements. SSRI-induced downregulation of the SERT may be a key component for the clinical response to SSRIs.

Validation of [123I]β-CIT SPECT to Assess Serotonin Transporters In Vivo in Humans: a Double-Blind, Placebo-Controlled, Crossover Study with the Selective Serotonin Reuptake Inhibitor Citalopram

“…Decreased binding of [ 123 I]b-CIT to SERTs after pretreatment with citalopram could be caused by decreased availability of SERTs due to blockage of SERTs by citalopram, by downregulation of the SERT protein, by a change in affinity of [ 123 I]b-CIT for the SERT, or by a combination of these factors. Benmansour et al (2002) showed that marked loss of SERT binding sites due to downregulation occurred in rats only after 10-15 days of SSRI treatment. Therefore, we think it is not likely that SERT downregulation in our subjects occurred within one day after only one dose of citalopram.…”

siRNA-mediated knockdown of the serotonin transporter in the adult mouse brain

“…20 The same infusion period is also required by SSRIs in order to produce a substantial downregulation of SERT. 6,7 Therefore, mice were infused with the SERT-targeting siRNA, a corresponding mmRNA, citalopram or vehicle for 2 weeks into the ventricular system. In situ hybridization analysis revealed a significant downregulation of SERT mRNA in the dorsal as well as median raphe of mice receiving siRNA (Figure 1a).…”

“…3,4 Emerging studies reveal downregulation of SERT as an adaptive consequence of sustained and high occupancy by chronically administered SSRIs. [5][6][7][8] The downregulation of SERT favorably potentiates the SSRI-mediated increase in the brain serotonergic neurotransmission. [6][7] Further, the lag time required by SSRIs to produce a substantial downregulation of SERT correlates well with the time needed for eliciting a full therapeutic response.…”

“…[5][6][7][8] The downregulation of SERT favorably potentiates the SSRI-mediated increase in the brain serotonergic neurotransmission. [6][7] Further, the lag time required by SSRIs to produce a substantial downregulation of SERT correlates well with the time needed for eliciting a full therapeutic response. Therefore, downregulation of SERT has been implicated in the antidepressant action of SSRIs.…”

Transient Neonatal Jitteriness due to Maternal Use of Sertraline (Zoloft®)

“…14 In this patient, the serotonin level was less than the reference range consistent with chronic exposure to sertraline prenatally. However, it is unclear whether the serotonin level or its enhanced neurotransmission with chronic exposure to sertraline contributes to the patient's symptoms.…”