Detailed pharmacological evaluation of methoxetamine (MXE), a novel psychoactive ketamine analogue—Behavioural, pharmacokinetic and metabolic studies in the Wistar rat

Horsley, Rachel Rutter; Lhotková, Eva; Hájková, Kateřina; Jurásek, Bronislav; Kuchař, Martin; Páleníček, Tomáš

doi:10.1016/j.brainresbull.2016.05.002

Cited by 36 publications

(30 citation statements)

References 39 publications

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“…Similarly, Horsley et al . () reported that MXE (10 and 40 mg·kg −1 , given s.c.) increased locomotor activity. While we did not test MXE doses higher than 5 mg·kg −1 , which we excluded after initial toxicological screening, we observed opposite motor effects induced by MXE (1 and 5 mg·kg −1 ).…”

Section: Discussionmentioning

confidence: 99%

“…Further differences are the phases of the diurnal cycle when the experiments were carried out (Halberstadt et al, ), the rat strain used (Horsley et al, ) and motor parameters analysed. In particular, we evaluated horizontal, vertical activity and distance travelled in standard motor activity cages, while in the other two studies, motor activity was quantified as number of crossings between any of the eight sections within the behavioural pattern monitor and by a descriptive statistic (spatial d) that calculated the spatial structure of locomotor paths (Halberstadt et al, ), or by trajectory length in cm (corrected for deviations less than 3 cm) over 5 min time blocks during 30 min sessions (Horsley et al, ). Remarkably, irrespective of the specific motor parameter affected by MXE and of the direction of its effects, all of the three studies indicated a biphasic effect of MXE on locomotor activity, as previously reported for ketamine and MK‐801 (Castagné et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of chemical similarities, MXE has been hypothesized to induce ketamine‐like effects (Hofer et al, ) and to produce a rapid antidepressant action (Coppola and Mondola, ). Preclinical studies have recently started investigating its pharmacokinetics, behavioural effects and underlying brain mechanisms (Hajkova et al, ; Horsley et al, ; Hondebrink et al, ). In rats, MXE was reported to induce conditioned place preference and maintain intravenous self‐administration behaviour (Botanas et al, ) and to substitute for ketamine in a drug self‐administration substitution study (Mutti et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Methoxetamine affects brain processing involved in emotional response in rats

Zanda

Fadda

Antinori

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEMethoxetamine (MXE) is a novel psychoactive substance that is emerging on the Internet and induces dissociative effects and acute toxicity. Its pharmacological effects have not yet been adequately investigated. EXPERIMENTAL APPROACHWe examined a range of behavioural effects induced by acute administration of MXE (0.5-5 mg·kg À1 ; i.p.) in rats and whether it causes rapid neuroadaptive molecular changes. KEY RESULTS MXE (0.5-5 mg·kgÀ1 ) affected motor activity in a dose-and time-dependent manner, inducing hypermotility and hypomotility at low and high doses respectively. At low and intermediate doses (0.5 and 1 mg·kg À1 ), MXE induced anxious and/or obsessive-compulsive traits (marble burying test), did not significantly increase sociability (social interaction test) or induce spatial anxiety (elevated plus maze test). At a high dose (5 mg·kg À1 ), MXE induced transient analgesia (tail-flick and hot-plate test), decreased social interaction time (social interaction test) and reduced immobility time while increasing swimming activity (forced swim test), suggesting an antidepressant effect. Acute MXE administration did not affect self-grooming behaviour at any dose tested. Immunohistochemical analysis showed that behaviourally active doses of MXE (1 and 5 mg·kg À1 ) increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex and hippocampus. CONCLUSIONS AND IMPLICATIONSMXE differentially affected motor activity, behaviour and emotional states in rats, depending on the dose tested. As reported for ketamine, phosphorylation of the ribosomal protein S6 was increased in MXE-treated animals, thus providing a 'molecular snapshot' of rapid neuroadaptive molecular changes induced by behaviourally active doses of MXE. Abbreviations

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Methoxetamine affects brain processing involved in emotional response in rats

Zanda

Fadda

Antinori

et al. 2017

British J Pharmacology

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“…The longer lasting effects compared to ketamine described in human case reports are confirmed in rats. Moreover, MXE accumulates in the brain, which can explain the increased psychological effects (both desired and adverse) and increased toxicity compared with ketamine (Horsley et al, 2016). The limited available in vitro studies indicate that MXE may resemble the pharmacology of ketamine, which main mechanism is antagonism of the glutamate N-methyl-D-aspartate (NMDA) receptor (Bergman, 1999).…”

Section: Introductionmentioning

confidence: 99%

Neuropharmacological characterization of the new psychoactive substance methoxetamine

et al. 2017

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a b s t r a c tThe use of new psychoactive substances (NPS) is steadily increasing. One commonly used NPS is methoxetamine (MXE), a ketamine analogue. Several adverse effects have been reported following MXE exposure, while only limited data are available on its neuropharmacological modes of action.We investigated the effects of MXE and ketamine on several endpoints using multiple in vitro models. These included rat primary cortical cells, human SH-SY5Y cells, human induced pluripotent stem cell (hiPSC)-derived iCell ® Neurons, DopaNeurons and astrocyte co-cultures, and human embryonic kidney (HEK293) cells. We investigated effects on several neurotransmitter receptors using single cell intracellular calcium [Ca 2þ ] i imaging, effects on neuronal activity using micro-electrode array (MEA) recordings and effects on human monoamine transporters using a fluorescence-based plate reader assay.In rat primary cortical cells, 10 mM MXE increased the glutamate-evoked increase in [Ca 2þ ] i , whereas 10 mM ketamine was without effect. MXE and ketamine did not affect voltage-gated calcium channels (VGCCs), but inhibited spontaneous neuronal activity (IC 50 0.5 mM and 1.2 mM respectively). In human SH-SY5Y cells, 10 mM MXE slightly inhibited the K Our combined in vitro data provide an urgently needed first insight into the multiple modes of action of MXE. The use of different models and different (neuronal) endpoints can be complementary in pharmacological profiling. Rapid in vitro screening methods as those presented here, could be of utmost importance for gaining a first mechanistic insight to aid the risk assessment of emerging NPS.

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“…Metabolites of phase II were also observed ( Wistar rat serum, brain, lungs, and liver. 44,54,55 NorDXE, as a major metabolite of DXE, is suggestive of being the main interest within the toxicological analysis. However, norDXE is also likely to be common metabolite for compounds such as eticyclidone or any other phenylcyclohexylamine differing in an alkyl moiety on the nitrogen.…”

Section: Phase II Metabolitesmentioning

confidence: 99%

Synthesis and identification of deschloroketamine metabolites in rats' urine and a quantification method for deschloroketamine and metabolites in rats' serum and brain tissue using liquid chromatography tandem mass spectrometry

Hájková

Jurásek

Čejka

et al. 2020

Drug Testing and Analysis

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Deschloroketamine (2‐(methylamino)‐2‐phenyl‐cyclohexanone) is a ketamine analog belonging to a group of dissociative anesthetics, which have been distributed within the illicit market since 2015. However, it was also being sold as ‘ketamine' misleading people to believe that they were getting genuine ketamine. Dissociative anesthetics have also come to the attention of the psychiatric field due to their potential properties in the treatment of depression. At present, there is a dearth of information on deschloroketamine related to its metabolism, biodistribution, and its mechanism of action. We have therefore carried out a metabolomics study for deschloroketamine via non‐targeted screening of urine samples employing liquid chromatography combined with high‐resolution mass spectrometry. We developed and validated a multiple reaction monitoring method using a triple quadrupole instrument to track metabolites of deschloroketamine. Furthermore, significant metabolites of deschloroketamine, (trans‐dihydrodeschloroketamine, cis‐ and trans‐dihydronordeschloroketamine, and nordeschloroketamine), were synthesized in‐house. The prepared standards were utilized in the developed multiple reaction monitoring method. The quantification method for serum samples provided intra‐day accuracy ranging from 86% to 112% with precision of 3% on average. The concentrations of cis/trans‐dihydronordeschloroketamines and trans‐dihydrodeschloroketamine were lower than 10 ng/mL, nordeschloroketamine and deschloroketamine ranged from 0.5 to 860 ng/mL in real samples. The quantification method for brain tissue provided intra‐day accuracy ranging from 80% to 125% with precision of 7% on average. The concentrations of cis/trans‐dihydronordeschloroketamines and trans‐dihydrodeschloroketamine ranged from 0.5 to 70 ng/g, nordeschloroketamine and deschloroketamine varied from 0.5 to 4700 ng/g in real samples.

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Detailed pharmacological evaluation of methoxetamine (MXE), a novel psychoactive ketamine analogue—Behavioural, pharmacokinetic and metabolic studies in the Wistar rat

Cited by 36 publications

References 39 publications

Methoxetamine affects brain processing involved in emotional response in rats

Methoxetamine affects brain processing involved in emotional response in rats

Neuropharmacological characterization of the new psychoactive substance methoxetamine

Synthesis and identification of deschloroketamine metabolites in rats' urine and a quantification method for deschloroketamine and metabolites in rats' serum and brain tissue using liquid chromatography tandem mass spectrometry

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