Abstract
A major problem in the treatment of depression is that many patients do not experience therapeutic benefit. The most commonly prescribed antidepressant drugs are the selective serotonin (5‐HT) reuptake inhibitors (SSRIs), which act by blocking the high‐affinity 5‐HT transporter (SERT). The increase in extracellular 5‐HT produced by SSRIs is thought to be critical to initiate downstream events needed for therapeutic effects. A potential explanation for their limited therapeutic efficacy is the recently characterized presence of low‐affinity, high‐capacity transporters for 5‐HT in brain, (e.g. organic cation transporters [OCTs]), which may limit the ability of SSRIs to increase extracellular 5‐HT. Decynium‐22 (D‐22) is an OCT blocker, and using this compound we uncovered a significant role for OCTs in 5‐HT uptake in SERT knockout mice, raising the possibility that pharmacological inactivation of OCTs might enhance the neurochemical and behavioral effects of SSRIs. Here we show that [3H]D‐22 binding sites are richly expressed in mouse hippocampus, and that D‐22 enhances the effects of the SSRI fluvoxamine to inhibit 5‐HT clearance and to produce antidepressant‐like activity. Our findings provide a mechanistic basis for poor therapeutic outcome following treatment with SSRIs, and point to D‐22‐sensitive transporters as novel targets for new antidepressant drugs with improved therapeutic potential. Supported by National Institutes of Health Grants R01 MH064489, R03 MH086708, Morrison Trust, and a NARSAD Independent Investigator Award.
Published Version
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