The ketamine-like compound methoxetamine substitutes for ketamine in the self-administration paradigm and enhances mesolimbic dopaminergic transmission

Abstract

This study, while confirming the reinforcing effects of MXE, highlights an electrophysiological and neurochemical profile predictive of its addictive properties.

Methoxetamine affects brain processing involved in emotional response in rats

“…However, MXE‐induced antinociceptive effects might involve different sites in the brain, including non‐NMDA glutamate receptors, and other (not glutamatergic) neurotransmission systems (Forman, ). Indeed, MXE displayed affinity for the 5‐HT transporter, the dopamine transporter and the noradrenaline transporter but not for σ receptors (Roth et al, ; Hondebrink et al, ), was found to significantly activate the mesolimbic dopaminergic system (Mutti et al, ) and to inhibit monoamine transporters more potently than ketamine (Hondebrink et al, ).…”

“…Rodent grooming behaviour consists of specific stereotyped patterns of sequential movements that can be affected by experimental manipulation, including administration of dopaminergic drugs (Kalueff et al, ). Given the reported stimulation by MXE of mesolimbic dopamine transmission (Mutti et al, ), we expected the time spent in self‐grooming to be increased following acute MXE administration. Thus, finding that MXE did not alter such a behaviour, even at a low dose previously showed to increase marble burying behaviour, was quite surprising.…”

“…In conclusion, our knowledge of the clinical effects of MXE originate from case reports of intoxication or self‐medication and self‐reported experiences described by users in Web discussion fora. We recently showed that MXE exerted discriminative stimulus effects similar to ketamine (Chiamulera et al, ) and induced clear rewarding effects in rats by stimulating mesolimbic dopaminergic transmission (Mutti et al, ). The present study adds further insight into the pharmacological effects of this new psychoactive substance by showing its ability to enhance repetitive/perseverative behaviour at low doses and to induce transient analgesia, social anxiety and antidepressant effects at high doses.…”

“…We recently showed that MXE fully generalize to ketamine interoceptive stimulus in a two‐lever operant drug discrimination paradigm in rats trained to discriminate ketamine from saline, similarly to the NMDA channel blocker MK‐801, thus exhibiting ketamine‐like discriminative stimulus properties (Chiamulera et al, ). In support of its abuse liability, following MXE administration we observed an enhanced level of dopamine in the rat nucleus accumbens shell (NAcS) and a dose‐dependent stimulation of the firing rate and burst firing of dopamine neurons in the ventral tegmental area projecting to the NAcS (Mutti et al, ). Intriguingly, MXE was recently reported to be used for self‐medication purposes to treat chronic foot pain (Maskell et al, ) and post‐traumatic stress disorder (Striebel et al, ), suggesting possible use as an analgesic and calming drug.…”

“…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, ). We recently showed that MXE fully generalize to ketamine interoceptive stimulus in a two‐lever operant drug discrimination paradigm in rats trained to discriminate ketamine from saline, similarly to the NMDA channel blocker MK‐801, thus exhibiting ketamine‐like discriminative stimulus properties (Chiamulera et al, ).…”