Antidepressant potential of organic cation transporter blockade: the role of norepinephrine (1144.5)

Abstract

Depression is a major health problem for which most patients are not effectively treated. This underscores a need to identify new targets for the development of antidepressants with improved efficacy. Our previous studies have shown that blockade of organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT) with decynium‐22 (D‐22) can produce antidepressant‐like effects, which are correlated with the ability of D‐22 to inhibit serotonin (5‐HT) clearance in brain, when the 5‐HT transporter (SERT) is pharmacologically or genetically compromised. In vitro studies show that OCT3 takes up norepinephrine (NE) more efficiently than 5‐HT, which raises the possibility that D‐22 might enhance the antidepressant‐like actions of drugs that block NE uptake via the NE transporter (NET). Using in vivo chronoamperometry, an electrochemical technique which allows second by second recording of extracellular biogenic amine concentrations, we show D‐22 increases time to clear NE from the extracellular space, and show D‐22 potentiates the effects of NET blockers venlafaxine (VEN) and desipramine (DMI) to increase clearance time of NE in the dentate gyrus and CA3 of the hippocampus. We next investigated if D‐22 can enhance the antidepressant‐like effects of VEN/DMI. Both VEN and DMI reduced immobility on the tail suspension test (TST), a test commonly used to assay antidepressant‐like activity of drugs in mice. Unlike the enhancing effect of D‐22 on increasing clearance time of NE, D‐22 did not enhance the antidepressant‐like effect of VEN/DMI in wild‐type mice. Ongoing studies are investigating the antidepressant‐like effect of D22 in SERT KO and heterozygous mice.Grant Funding Source: Supported by MH093320 (LD & WK), MH064489 (LD), NARSAD (LD) and UL1RR025767 (R25 START UP).