Antidepressant‐like Effects of Ketamine in Serotonin Transporter Knockout Mice and Organic Cation Transporter 3 Knockout Mice
Melodi Ann Bowman, Melissa Vitela, W. Anthony Owens, Wouter Koek, Lynette C. Daws
The FASEB Journal April 1, 2017 DOI: 10.1096/fasebj.31.1_supplement.813.9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | SERT knockout and wildtype adult mice on a C57BL/6J background, and OCT3 knockout mice |
| Intervention | Ketamine |
| Measures | Tail suspension test, forced swim test |
| Topics | Esketamine Ketamine Serotonin |
| Key points | Ketamine decreased serotonin clearance rate and increased signal amplitude in the CA3 region of the hippocampus. Ketamine produced antidepressant-like effects only in SERT knockout mice, not wildtype mice, and this effect was attenuated in OCT3 knockout mice. The authors suggest that OCT3 may play a role in ketamine's antidepressant-like effects. |
Abstract
Twenty percent of adults are diagnosed with major depressive disorder, which is typically treated with selective serotonin reuptake inhibitors. However, this type of medication takes 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 while another found an inhibition of serotonin uptake following ketamine treatment. Together, these studies suggest a role for serotonin in the antidepressant‐like effects of ketamine, and putatively one involving the serotonin transporter (SERT). In order to investigate this, we performed in vivo chronoamperometry. A nafion coated carbon fiber electrode and four barrel micropipette was inserted into the CA3 region of the hippocampus and serotonin, ketamine, or vehicle was applied exogenously. Our results showed a decrease in clearance rate of serotonin after application of ketamine as well as an increase in signal amplitude. To further elucidate this effect, we examined antidepressant‐like effects of ketamine in SERT knockout mice bred on a C57BL/6J background. SERT knockout and wildtype adult mice were treated with vehicle or ketamine and tested in the tail suspension test. Ketamine had antidepressant‐like effects only in SERT knockout mice. Taken together with published findings that SERT knockout mice have increased expression of organic cation transporter 3 (OCT3) relative to wildtype littermates, and that blockade of OCT3 produces antidepressant‐like effects and inhibits serotonin uptake, we next examined the antidepressant‐like effects of ketamine in OCT3 knockout mice using the forced swim test. Our results indicate that the antidepressant‐like effect of ketamine is attenuated in the OCT3 knockout mice. Ongoing studies are investigating the dose‐response relationship of these effects in SERT and OCT3 knockout mice to investigate a potential role for OCT3 in antidepressant‐like effects of ketamine. Support or Funding Information This project was supported by NIH training grant T32 NS082145 funded by the Jointly Sponsored NIH Predoctoral Training Program in Neurosciences and by R01 MH093320 and R01 MH106978
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| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |