Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Abstract

Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys underwent four positron emission tomography measurements with [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([ 11 C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ 11 C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT 1A -R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [ 11 C]DASB. No significant changes were observed in either 5-HT 1A -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity. This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

“…isoflurane, have been shown to decrease cortical extracellular serotonin concentration (Mukaida et al 2007) and to increase [ 3 H]escitalopram binding in rats (Elfving et al 2003). Moreover, in a paradigm more similar to the current study, sub-anaesthetic doses of ketamine have recently been shown to decrease [ 11 C]DASB binding by up to 30 % in NHPs (Yamamoto et al 2013;Yamanaka et al 2014). In the current and previous SERT occupancy studies (Batis et al 2012;Cosgrove et al 2010), ketamine was used to induce anaesthesia and baseline PET measurements may therefore be more affected by ketamine than the post-SSRI measurements.…”

Effects of anesthetics on vesicular monoamine transporter type 2 binding to 18 F-FP-(+)-DTBZ: a biodistribution study in rat brain

“…This is consistent with a recent work by Shigeyyuki et al, who demonstrated a transient increase of serotonin levels in the extracellular fluid caused by ketamine [47]. The authors concluded that the increase of serotonin level was due to inhibition of SERT since its availability was reduced meanwhile 5-HT 1A receptor was unchanged.…”

“…Some investigators have reported that ketamine affects several neuronal transmission systems, such as dopamine receptor and transporter [43][44][45][46], serotonin receptor and transporter [47], glutamate receptor [48], etc. However, interference of ketamine with VMAT2, another important target in the central nervous system, which mediating monoaminergic transmission, is still unknown.…”

Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression

“…Indeed, ketamine possesses a rich pharmacology, including activity at sigma receptors (123,124). Moreover, actions within dopaminergic (125)(126)(127) or serotonergic (128)(129)(130)(131)(132) systems have also been postulated as alternate mechanisms for ketamine's antidepressant effects. Conversely, ketamine's unique antidepressant properties may be attributable to distinctions in its pharmacodynamic activity within the NMDA receptor (34,122).…”