Methoxphenidine (MXP) induced abnormalities: Addictive and schizophrenia‐related behaviours based on an imbalance of neurochemicals in the brain

Abstract

Background and Purpose Methoxphenidine is a dissociative‐based novel psychoactive designer drug. Although fatal accidents from methoxphenidine abuse have been reported, recreational use of the drug continues. We aim to provide scientific supportfor legal regulation of recreational abuse of methoxphenidine by demonstrating its the pharmacological action. Experimental Approach Addictive potential of methoxphenidine was examined using intravenous self‐administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests (open field test, elevated plus maze test, novel object recognition test, social interaction test and tail suspension test) performed to assess whether methoxphenidine caused schizophrenia‐related symptoms in mice. Additionally, neurotransmitter enzyme‐linked immunosorbent assay and western blot were used to confirm methoxphenidine‐induced neurochemical changes in specific brain regions related to abnormal behaviours. Key Results Methoxphenidine caused addictive behaviours via reinforcing and rewarding effects. Consistently, methoxphenidine induced over‐activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, methoxphenidine caused all categories of schizophrenia‐related symptoms, including positive symptoms (hyperactivity, impulsivity), negative symptoms (anxiety, social withdrawal, depression) and cognitive impairment. Consistently, methoxphenidine led to the disruption of the hippocampal–prefrontal cortex pathway that is considered to be pathological involved in schizophrenia. Conclusions and Implications We demonastrate that methoxphenidine causes addictive and schizophrenia‐like behaviours and induces neurochemical changes in brain regions associated with these behaviours. We propose that methoxphenidine could be used in developing useful animal disease models and that it also requires legal restrictions on its recreational use.

A structural spectroscopic study of dissociative anaesthetic methoxphenidine

“…In experiments in rodents focused on the chronic administration of methoxphenidine, Hur et al observed hyperactivity, increased impulsivity, recognition memory dysfunction, social withdrawal, depressive-like behaviour and schizophrenia-relevant symptoms. 9 Compared to controls the MXP treated animals had significantly increased expression levels of CAMK2, DAT (dopamine transporter, SLC6A3), p-DAT, D 1 receptor, and TH and an increase in the p-DAT/DAT ratio. In comparison to its structural analogue diphenidine, MXP is a slightly less potent inhibitor of NET and a significantly less potent inhibitor of DAT.…”

“…10,11 According to unofficial user experiences, MXP is less active than common arylcyclohexylamines like methoxetamine, deschloroketamine or ketamine, 12,13 yet it may be quite addictive. 9,14–16 Despite the lower potency, several intoxications were associated with this substance to date. 12,13 Symptoms like rhabdomyolysis, ischemic cerebral disease, acute kidney failure or other serious psychic and somatic complications can also occur during the intoxications.…”

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents

“…Experimental animals were selected on the basis of previous studies with consideration of the sensitivity to each behavioural experiment [32]. Studies were designed to generate equally sized groups using randomization.…”

“…This test was performed to determine whether Mepirapim treatment changed neurotransmitter levels in each brain region (VTA and NAc). Minor modifications were made to the previously reported experimental design [32]. Brain samples from mice treated with the vehicle or Mepirapim (1 or 3 mg•kg −1 ) during the CPP and tetrad tests were used (n = 5 per group).…”

Intriguing Cytotoxicity of the Street Dissociative Anesthetic Methoxphenidine: Unexpected Impurities Spotted

“…MXP in combination with other dissociatives may lead to delusions, sedation, amnesia, nausea, and even respiratory depression [22]. Moreover, likewise, with other dissociative anesthetics [24,25], methoxphenidine may also be addictive [22,26,27] and may produce various symptoms related to schizophrenia [26]. Yet, even though it has already been available on the black market for at least half a decade, there remains a lack of information on its pharmacological and physico-chemical properties.…”