Methoxetamine affects brain processing involved in emotional response in rats

Background and Purpose: Methoxetamine (MXE) is a novel psychoactive substance that is emerging on the Internet and induces dissociative effects and acute toxicity. Its pharmacological effects have not yet been adequately investigated. Experimental Approach: We examined a range of behavioural effects induced by acute administration of MXE (0.5–5 mg·kg−1; i.p.) in rats and whether it causes rapid neuroadaptive molecular changes. Key Results: MXE (0.5–5 mg·kg−1) affected motor activity in a dose- and time-dependent manner, inducing hypermotility and hypomotility at low and high doses respectively. At low and intermediate doses (0.5 and 1 mg·kg−1), MXE induced anxious and/or obsessive–compulsive traits (marble burying test), did not significantly increase sociability (social interaction test) or induce spatial anxiety (elevated plus maze test). At a high dose (5 mg·kg−1), MXE induced transient analgesia (tail-flick and hot-plate test), decreased social interaction time (social interaction test) and reduced immobility time while increasing swimming activity (forced swim test), suggesting an antidepressant effect. Acute MXE administration did not affect self-grooming behaviour at any dose tested. Immunohistochemical analysis showed that behaviourally active doses of MXE (1 and 5 mg·kg−1) increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex and hippocampus. Conclusions and Implications: MXE differentially affected motor activity, behaviour and emotional states in rats, depending on the dose tested. As reported for ketamine, phosphorylation of the ribosomal protein S6 was increased in MXE-treated animals, thus providing a ‘molecular snapshot’ of rapid neuroadaptive molecular changes induced by behaviourally active doses of MXE