Investigating the Role of Serotonin Transporter, Plasma Membrane Monoamine Transporter, and Organic Cation Transporter 3 in the Antidepressant‐like Effects of Ketamine

Abstract

Twenty percent of adults are diagnosed with major depressive disorder, which is typically treated with selective serotonin reuptake inhibitors (SSRIs). However, SSRIs take approximately six weeks to produce therapeutic effects. Recently, low doses of ketamine, a noncompetitive N‐methyl‐ D‐aspartate (NMDA) receptor antagonist, have been shown to produce rapid and long‐lasting antidepressant effects. Studies that have begun to examine the mechanisms underlying these effects have focused on intracellular changes mediated by NMDA and/or AMPA receptors. However, the traditional view of the etiology of depression involves the need for an increase in extracellular serotonin to regulate mood. Surprisingly, there appears to be little research into the effects of ketamine on serotonin. One study found an increase in extracellular serotonin following ketamine, consistent with results from another study showing that ketamine inhibited serotonin uptake. Together, these findings suggest a role for serotonin in the antidepressant‐like effects of ketamine, and putatively one involving transporters capable of serotonin uptake. The serotonin transporter (SERT) is an obvious candidate, but recent evidence points to the plasma membrane monoamine transporter (PMAT) and organic cation transporter (OCT3) as important players in serotonin uptake as well. In order to investigate a role for these transporters in the action of ketamine to inhibit serotonin uptake, we used in vivo chronoamperometry to measure serotonin clearance from extracellular fluid of CA3 region of the hippocampus. In wildtype mice, ketamine robustly inhibited serotonin clearance. Ongoing chronoamperometry studies are using knockout lines of SERT, PMAT and OCT3 mice to parse apart their roles in the action of ketamine to inhibit serotonin clearance. Parallel studies using these knockout (KO) lines in the forced swim test support the involvement of all three transporters in the antidepressant‐like effect of ketamine. As expected, ketamine (32 mg/kg) produced robust antidepressant‐like effects in wildtype mice, but in marked contrast, was without effect in SERT KO, PMAT KO, and OCT3 KO mice. Ketamine did not influence locomotor activity in SERT KO and wildtype mice, ruling out differences in the action of ketamine on general activity accounting for the contrasting effect of ketamine in the FST between these genotypes. Experiments assessing the locomotor actions of ketamine in PMAT KO and OCT3 KO mice are ongoing. Together, these data suggest that blockade of SERT, PMAT, and/or OCT3 may be important for the antidepressant‐like effects of ketamine.Support or Funding InformationR01 MH093320R01 MH106978T32 NS082145This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.