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The ketamine-like compound methoxetamine substitutes for ketamine in the self-administration paradigm and enhances mesolimbic dopaminergic transmission

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Abstract

Rationale

Recently, an increasing number of emergency cases due to a novel ketamine-like drug, methoxetamine (MXE), were reported in several countries. However, very little is known about the neuropsychopharmacological and reinforcing profile of this compound.

Objectives

Our study aims to investigate the effects of MXE on self-administration (SA) behaviour in comparison to ketamine and on dopaminergic transmission.

Methods

A SA substitution study was performed in male rats trained to intravenously (IV) self-administer ketamine. At responding stability, rats were exposed to sequential phases of MXE substitution at different dosages (starting from 0.5 and then decreasing to 0.25 and 0.125 mg/kg). Standard electrophysiological techniques were used to record changes in firing activities of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (NAc) shell after acute injection of cumulative doses of MXE (0.031–0.5 mg/kg IV). Finally, in vivo microdialysis was performed in freely moving rats to evaluate the effect of acute MXE administration (0.125, 0.25 and 0.5 mg/kg IV) on dopamine release in the NAc shell.

Results

MXE 0.125 and 0.25 mg/kg, but not 0.5 mg/kg, substituted for ketamine SA. MXE also induced a dose-dependent stimulation of firing rate (p < 0.0001) and burst firing (p < 0.05) of NAc-projecting VTA dopamine neurons. Consistently, MXE significantly (p < 0.05) increased dopamine extracellular levels in the NAc shell at 0.5 and 0.25 mg/kg with different time onsets, i.e. at 40 and 100 min, respectively.

Conclusions

This study, while confirming the reinforcing effects of MXE, highlights an electrophysiological and neurochemical profile predictive of its addictive properties.

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Acknowledgments

Funded by ‘Joint Project 2012’ from University of Verona, in collaboration with C.N.R. Institute of Neuroscience, Cagliari, and University of Cagliari and a grant from Fondazione Banco di Sardegna 2014.

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Authors and Affiliations

  1. Neuropsychopharmacology Lab., Sect. Pharmacology, Dept. Diagnostic & Public Health, Univ. Verona, Verona, Italy

    Anna Mutti, Laura Padovani, Laura Mancini & Cristiano Chiamulera

  2. Dept. Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Univ. Cagliari, Monserrato, Italy

    Sonia Aroni, Paola Fadda & Roberto Collu

  3. Neuroscience Institute—Cagliari, National Research Council of Italy (CNR), Monserrato, Italy

    Anna Lisa Muntoni & Liana Fattore

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  1. Anna Mutti
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  2. Sonia Aroni
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Correspondence to Anna Mutti.

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Mutti, A., Aroni, S., Fadda, P. et al. The ketamine-like compound methoxetamine substitutes for ketamine in the self-administration paradigm and enhances mesolimbic dopaminergic transmission. Psychopharmacology 233, 2241–2251 (2016). https://doi.org/10.1007/s00213-016-4275-0

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