Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice

Abstract

Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine’s ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine’s antidepressant mechanism of action. Combined with what is already known about ketamine’s action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine’s abuse potential but have superior efficacy in treating depression.

Harnessing the Neurobiology of Resilience to Protect the Mental Well-Being of Healthcare Workers During the COVID-19 Pandemic

“…• The experimental use of 5HT 4 receptor agonists in reducing anxiety and depressive symptoms in healthcare workers exposed to chronic stress (Chen et al, 2020b). • The use of ketamine, already approved for the acute treatment of depression and suicidal behavior in humans, in subjects at high risk of pandemic-related stress (McGhee et al, 2008;Weinbroum, 2021); the efficacy of this drug appears to depend on intact monoamine pathways (Bowman et al, 2020).…”

“…Research in mice suggests that the noradrenergic system plays a particular role in influencing resilience to chronic stress ( Isingrini et al, 2016 ), and that the activation of a specific serotonin receptor subtype (5HT 4 ) reduces both fear-like and depressive-like responses to chronic stress ( Chen et al, 2020b ). Drugs that putatively influence resilience via other receptors, such as ketamine, have also been shown to depend on intact monoamine systems for their effects in preventing stress-induced depression ( Brachman et al, 2016 ; Bowman et al, 2020 ).…”

“…The use of ketamine, already approved for the acute treatment of depression and suicidal behavior in humans, in subjects at high risk of pandemic-related stress ( McGhee et al, 2008 ; Weinbroum, 2021 ); the efficacy of this drug appears to depend on intact monoamine pathways ( Bowman et al, 2020 ).…”

The Ketamine Antidepressant Story: New Insights

“…Similar findings were observed in mice lacking the membrane monoamine transporter (PMAT). Of note, high-speed chronoamperometry performed during in vivo studies of the hippocampal CA3 indicated that ketamine prevented the clearance of serotonin in wild-type mice, but failed to achieve this in SERT or PMAT transgenic mice [87].…”

Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations

“…Interestingly, the anesthetic drug ketamine has an antidepressant action. In the paper “Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice”, Bowman et al investigated whether this effect of ketamine is due to an influence on extracellular serotonin concentration [ 6 ]. They demonstrated that ketamine decreases serotonin clearance from the Cornu Ammonis (CA) 3 region of the murine hippocampus in vivo, probably by acting on the serotonin transporters (SERT) and the plasma membrane monoamine transporter (PMATs).…”