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

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.