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

Background and purpose Methoxphenidine (MXP) is a dissociative-based novel psychoactive designer drug. Although fatal accidents from MXP abuse have been reported, recreational use of the drug continues. We aim to provide scientific support, in this study, for legal regulation of recreational abuse of MXP by demonstrating the pharmacological effects of the compound. Experimental approach Addictive potential of MXP was confirmed by intravenous self-administration test with rats and conditioned place preference test with mice. Further, a series of behavioural tests were performed to assess whether MXP administration caused schizophrenia-related symptoms in mice - open field test; elevated plus maze test; novel object recognition test; social interaction test; tail suspension test. Additionally, neurotransmitter enzyme-linked immunosorbent assay and western blot were used to confirm MXP-induced neurochemical maladaptation in specific brain regions related to abnormal behaviours. Key results MXP treatment produced addictive behaviours through reinforcing and rewarding effects. Consistently, MXP administration induced over-activation of dopamine pathways in the nuclear accumbens, indicating activation of the brain reward circuit. Also, MXP administration caused all categories of schizophrenia-related symptoms, including positive symptoms (hyperactivity, impulsivity); negative symptoms (anxiety, social withdrawal, depression); cognitive impairment. Consistently, MXP treatment led to the disruption of the hippocampal-prefrontal cortex pathway that is considered a pathological cause of schizophrenia. Conclusions and implications We confirm that administration of MXP causes addictive and schizophrenia-relevant behaviours. Further, we demonstrate that MXP treatment induces neurochemical maladaptation in brain regions associated with addiction and schizophrenia. We propose, based on these results, that MXP could be used to establish useful animal disease models, and requires legal restrictions on recreational abuse.