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.
Highlights
Suicide rates have increased dramatically in recent years [1], and treatment resistant depression is a leading cause of suicide [2]
Great interest has been generated from clinical studies showing that a single dose of ketamine produces rapid, dramatic, and sustained depression symptom relief, even in individuals suffering from treatment resistant depression [4,5,6]
Using a separate cohort of mice, we examined serotonin clearance in the nucleus accumbens (NAcc) in order to determine if the lack of difference in serotonin clearance time in CA3 region of hippocampus between plasma membrane monoamine transporter (PMAT)+/+ and PMAT−/− mice generalized to other brain regions
Summary
Suicide rates have increased dramatically in recent years [1], and treatment resistant depression is a leading cause of suicide [2]. Most preclinical studies have focused on how blockade of NMDA receptors can exert antidepressant-like effects [8]. Ketamine triggers intracellular signaling pathways, including eukaryotic elongation factor 2 (eEF2) kinase, resulting in rapid increases in brain derived neurotrophic factor (BDNF) protein translation [8,9]. This increase in BDNF activates the mammalian target of rapamycin (mTOR) pathway, which in turn induces rapid synaptogenesis. This is viewed as the primary mechanism underlying ketamine’s antidepressant-like effects in preclinical studies [8,10]. Growing attention is turning to ketamine’s ability to increase extracellular serotonin
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