Evaluation of the neurochemical effects of methoxetamine using brain microdialysis in mice

Abstract

The ketamine analogue, 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone (methoxetamine) has emerged as a drug of abuse. Both methoxetamine and ketamine are antagonists of glutamate N-methyl-D-asparate receptors, and several case reports show that methoxetamine produces similar schizophrenia-like symptoms and hallucinations to ketamine. Although methoxetamine is believed to change levels of dopamine, glutamate, and serotonin in the brain, few studies thus far have examined these effects. We investigated the influence of methoxetamine on dopamine and serotonin concentrations using microdialysis and high performance liquid chromatography with electrochemical detection. To reveal the effects of methoxetamine, we monitored dopamine and serotonin concentrations in several brain areas [striatum, nucleus accumbens, and prefrontal cortex (mPFC)] after an administration of 20 mg/kg of methoxetamine. We compared the effects of methoxetamine with those of ketamine using two ketamine doses. Methoxetamine increased dopamine and serotonin concentrations most robustly in the mPFC. In addition, its effects were stronger than those of ketamine at the same molar dose, suggesting that methoxetamine causes schizophrenia-like symptoms and hallucinations by increasing the dopamine and serotonin concentrations. We conclude that consumption of methoxetamine may be more dangerous than consumption of ketamine.

The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents

“…Indeed, like other uncompetitive NMDAR antagonists (Moreton et al, 1977; Balaster, 1986; Marglin et al, 1989; Marquis et al, 1989; Suzuki et al, 1999), there is evidence that MXE produces rewarding effects in laboratory animals (Botanas et al, 2015). MXE also produces robust increases in DA and 5-HT release in prefrontal cortex (Fuchigami et al, 2015), effects that also occur with PCP and ketamine and are thought to underlie many of their hallucinogenic and behavioral effects. Taken together, these findings indicate that MXE is likely to produce roughly the same subjective effects and abuse potential as PCP and ketamine.…”

Phencyclidine-like in vivo effects of methoxetamine in mice and rats

“…In addition to structural similarities between MXE and PCP, MXE is also a high affinity ligand for the PCP-site on the glutamate N -methyl-D-aspartate (NMDA) receptor with an affinity value (p K i = 6.59 nM) comparable to that of PCP itself (p K i = 7.23 nM (Roth et al , 2013). Moreover, MXE is a high affinity reuptake inhibitor at monoamine transporters (especially the serotonin transporter [SERT]) as measured in vitro (Hondebrink et al , 2017), stimulates the firing rate of dopamine neurons in the ventral tegmental area and increases extracellular dopamine levels in the nucleus accumbens of awake, freely-moving Sprague-Dawley rats (Mutti et al , 2016), and increases extracellular dopamine and serotonin concentrations in the medial prefrontal cortex of awake, freely-moving ddY mice (Fuchigami et al , 2015). Similar to MXE, PCP increases extracellular concentrations of dopamine, serotonin, and norepinephrine in the medial prefrontal cortex of Sprague-Dawley and Wistar rats (Quarta & Large, 2011; Etou et al , 1998)…”