The ketamine-like compound methoxetamine substitutes for ketamine in the self-administration paradigm and enhances mesolimbic dopaminergic transmission.
Anna Mutti, Sonia Aroni, Paola Fadda, Laura Padovani, Laura Mancini, Roberto Collu, Anna Lisa Muntoni, Liana Fattore, Cristiano Chiamulera
Psychopharmacology June 1, 2016 DOI: 10.1007/s00213-016-4275-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Self-administration substitution study with electrophysiology and microdialysis Peer reviewed |
|---|---|
| Population | Male rats |
| Interventions | Methoxetamine Ketamine |
| Dose | 0.125, 0.25, and 0.5 mg/kg |
| Topics | Ketamine Esketamine |
| Keywords | Abuse liability Dopamine Drug substitution Methoxetamine mxe Nucleus accumbens Reward Self-administration Vta |
| Key points | Low doses of MXE (0.125 and 0.25 mg/kg) substitute for ketamine self-administration and increase dopamine neuron activity and dopamine release in the nucleus accumbens shell, indicating addictive potential. |
Abstract
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. Our study aims to investigate the effects of MXE on self-administration (SA) behaviour in comparison to ketamine and on dopaminergic transmission. 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. 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. This study, while confirming the reinforcing effects of MXE, highlights an electrophysiological and neurochemical profile predictive of its addictive properties.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 16
- The abuse liability of ketamine: A scoping review of preclinical and clinical studies. Journal of Psychiatric Research May 1, 2022
- Sex and Gender Differences in the Effects of Novel Psychoactive Substances. Brain Sciences September 3, 2020
- Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia Neurotoxicity Research July 1, 2017
- A combined toxicokinetic and metabolic approach to investigate deschloro-N-ethylketamine exposure in a multidrug user. Journal of Pharmaceutical and Biomedical Analysis June 15, 2024
- New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat. Experimental Neurology November 1, 2021
and 11 more in the library
Cites 23
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- Phenomenon of new drugs on the Internet: the case of ketamine derivative methoxetamine Human Psychopharmacology: Clinical and Experimental March 1, 2012
- The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor. PLoS One June 14, 2016
- From “Special K” to “Special M”: The Evolution of the Recreational Use of Ketamine and Methoxetamine CNS Neuroscience & Therapeutics June 1, 2013
- Methoxetamine (MXE) – A Phenomenological Study of Experiences Induced by a “Legal High” from the Internet Journal of Psychoactive Drugs July 1, 2013
and 18 more in the library