title: Detailed pharmacological evaluation of methoxetamine (MXE), a novel psychoactive ketamine analogue-Behavioural, pharmacokinetic and metabolic studies in the Wistar rat.
abstract: Methoxetamine (MXE) is a novel psychoactive compound (NPS) that emerged in 2010 as a substitute for the dissociative anaesthetic ketamine. MXE has a reputation of carrying a lower risk of harm than ketamine, however a number of deaths have been reported. Currently very little is known about the psychopharmacological effects of this compound or its toxicity; therefore we tested, in Wistar rats, the effects of MXE in a series of behavioural tasks, measured its pharmacokinetics and urinary metabolites. Locomotor activity and its spatial characteristics (in the open field) and sensorimotor gating (prepulse inhibition; PPI) were evaluated after 5, 10 and 40mg/kg subcutaneous (sc.) MXE. Pharmacokinetics and brain: serum ratios were evaluated after 10mg/kg sc. MXE so that peak drug concentration data could be used to complement interpretation of maximal behavioural effects. Finally, quantification of metabolites in rat urine collected over 24h was performed after single bolus of MXE 40mg/kg sc. 5 and 10mg/kg MXE induced significant locomotor stimulation, in addition it increased thigmotaxis and decreased time spent in the centre of the open field (indicative of anxiogenesis). By contrast, 40mg/kg reduced locomotion and increased time spent in the centre of the arena, suggesting sedation/anaesthesia or stereotypy. The duration of effects was present for at least 60-90min, although for 5mg/kg, locomotion diminished after 60min. MXE decreased baseline acoustic startle response (ASR) and disrupted PPI, irrespective of testing-onset. MXE (all doses) reduced habituation but only at 60min. Maximal brain levels of MXE were observed 30min after administration, remained high at 60min and progressively declined to around zero after six hours. MXE accumulated in the brain; the brain: serum ratio was between 2.06 and 2.93 throughout the whole observation. The most abundant urinary metabolite was O-desmethylmethoxetamine followed by normethoxetamine. To conclude, MXE acts behaviourally as a typical dissociative anaesthetic with stimulant and anxiogenic effects at lower doses, sedative/anaesthetic effects at higher doses, and as a disruptor of sensorimotor gating. Its duration of action exceeds that of ketamine which is consistent with reports from MXE users. The accumulation of the drug in brain tissue might reflect MXE's stronger potency compared to ketamine and indicate increased toxicity.
authors.affiliation: National Institute of Mental Health CZ, Topolová 748, Klecany, 250 67, Czech Republic.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Horsley
authors.affiliation: National Institute of Mental Health CZ, Topolová 748, Klecany, 250 67, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Lhotkova
authors.affiliation: National Institute of Mental Health CZ, Topolová 748, Klecany, 250 67, Czech Republic; Forensic Laboratory of Biologically Active Compounds, University of Chemistry and Technology Prague, Technická 5, Prague 6, 166 28, Czech Republic; Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technická 5, Prague 6, Dejvice, 166 28, Czech Republic.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hajkova
authors.affiliation: Forensic Laboratory of Biologically Active Compounds, University of Chemistry and Technology Prague, Technická 5, Prague 6, 166 28, Czech Republic; Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 5, Prague 6, 166 28, Czech Republic.
authors.forename: Bronislav
authors.initials: B
authors.lastname: Jurasek
authors.affiliation: National Institute of Mental Health CZ, Topolová 748, Klecany, 250 67, Czech Republic; Forensic Laboratory of Biologically Active Compounds, University of Chemistry and Technology Prague, Technická 5, Prague 6, 166 28, Czech Republic; Department of Chemistry of Natural Compounds, University of Chemistry and Technology Prague, Technická 5, Prague 6, 166 28, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Kuchar
authors.affiliation: National Institute of Mental Health CZ, Topolová 748, Klecany, 250 67, Czech Republic. Electronic address: tomas.palenicek@nudz.cz.
authors.forename: Tomas
authors.initials: T
authors.lastname: Palenicek
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003512:Cyclohexanones / Q000378:metabolism* / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000378:metabolism* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D065808:Prepulse Inhibition / Q000187:drug effects; D011619:Psychotropic Drugs / Q000378:metabolism* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003512:Cyclohexanones; D003514:Cyclohexylamines; D011619:Psychotropic Drugs; C569113:2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone
keywords: Metabolism; Methoxetamine; Open field; Pharmacokinetics; Prepulse inhibition; Wistar rat