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Uncovering interactions between organic cation transporters and monamine systems: implications for novel antidepressant therapies
Author(s) -
Apple Deana Marie,
Horton Rebecca E,
Vitela Melissa,
Koek Wouter,
Daws Lynette C
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1100.1
Subject(s) - antidepressant , organic cation transport proteins , monoamine neurotransmitter , serotonin , transporter , serotonin transporter , pharmacology , reuptake inhibitor , reuptake , chemistry , medicine , psychiatry , receptor , biochemistry , gene , anxiety
Depression is an important mental health problem. The most commonly prescribed antidepressants are selective serotonin (5‐ HT) reuptake inhibitors (SSRIs), which increase extracellular 5‐HT by blocking the high‐affinity 5‐HT transporter (SERT). Unfortunately, in many patients, SSRIs do not effectively relieve depression symptoms. A potential explanation for their limited effectiveness is the presence of low‐affinity, high‐capacity organic cation transporters (OCTs), which can take up 5‐HT, and may limit the ability of SSRIs to increase extracellular 5‐HT. Using the OCT blocker decynium‐22 (D‐22), we uncovered a significant role for OCTs in 5‐HT uptake when SERT is genetically or pharmacologically compromised. Here we show that in mice lacking the OCT3 subtype, D‐22 no longer enhances SSRI‐induced inhibition of 5‐HT clearance and antidepressant‐like effects. We extend these findings by examining the effects of chronic administration of D‐22, alone and together with monoamine uptake inhibitors, on 5‐HT uptake and antidepressant‐like activity in wild type and OCT3 −/− mice. Our results provide further evidence that OCT3 may contribute to the poor therapeutic outcome of SSRI treatment, and points to D‐22‐sensitive transporters, putatively OCT3, as novel targets for new antidepressant drugs with improved therapeutic potential. Supported by R01 MH093320 (LD & WK), R01 MH064489 (LD), and NARSAD (LD).