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The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents

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Abstract

Rationale

Methoxetamine (MXE) is a ketamine analog sold online that has been subject to widespread abuse for its dissociative and hallucinogenic effects. Previous studies have shown that MXE has high affinity for the phencyclidine (PCP) binding site located within the channel pore of the NMDA receptor (NMDAR), but little is known about its behavioral effects. Dissociative anesthetics such as ketamine and PCP produce a characteristic behavioral profile in rats that includes locomotor hyperactivity and disruption of prepulse inhibition (PPI) of acoustic startle.

Methods

The goal of the present investigation was to determine whether MXE produces PCP-like effects in Sprague-Dawley rats using the PPI paradigm and the behavioral pattern monitor (BPM), which enables analyses of patterns of locomotor activity and investigatory behavior. PPI studies were conducted with several other uncompetitive NMDAR antagonists that produce dissociative effects in humans, including PCP, the S-(+) and R-(−) isomers of ketamine, and N-allylnormetazocine (NANM; SKF-10,047).

Results

MXE disrupted PPI when administered at 3 and 10 mg/kg SC. The rank order of potency of MXE and the other test compounds in the PPI paradigm (PCP > MXE > S-(+)-ketamine > NANM > R-(−)-ketamine) parallels their affinities for the PCP binding site reported in the literature. When tested in the BPM, 10 mg/kg MXE induced locomotor hyperactivity, reduced the number of rearings, increased the roughness of locomotor paths, and produced perseverative patterns of locomotion. Administration of PCP (2.25 and 6.75 mg/kg, SC) produced a similar profile of effects in the BPM.

Conclusions

These results indicate that MXE produces a behavioral profile similar to that of other psychotomimetic uncompetitive NMDAR antagonists. Our findings support the classification of MXE as a dissociative drug and suggest that it likely has effects and abuse potential similar to that of PCP and ketamine.

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Acknowledgments

This work was supported by NIMH K01 MH100644, NIDA R01 DA002925, and the Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center.

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Authors and Affiliations

  1. Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, 92093-0804, La Jolla, CA, USA

    Adam L. Halberstadt, James Hyun, Mahalah R. Buell & Susan B. Powell

  2. Department of Biology, University of California San Diego, La Jolla, CA, USA

    Natalia Slepak

  3. Research Service, VA San Diego Healthcare System, San Diego, CA, USA

    Adam L. Halberstadt & Susan B. Powell

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  1. Adam L. Halberstadt
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Correspondence to Adam L. Halberstadt.

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Funding

Dr. Halberstadt’s work has been funded by NIH, the Brain & Behavior Research Foundation, and L-3 Communications. Dr. Powell’s work has been funded by NIH and Acadia Pharmaceuticals. Mahalah Buell, James Hyun, and Natasha Slepak have not received compensation for professional services during the past 3 years.

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The authors have no conflicts of interest to disclose.

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Figure S1

Effect of ketamine stereoisomers on prepulse inhibition. (Top panel) Effect of S-(+)-ketamine. (Bottom panel) Effect of R-(–)-ketamine. Values represent mean ± SEM for each group. *p < 0.05, **p < 0.01, significantly different from vehicle control. (GIF 128 kb)

High resolution image (TIF 379 kb)

Figure S2

Effect of N-allylnormetazocine on prepulse inhibition. Values represent mean ± SEM for each group. **p < 0.01, significantly different from vehicle control. (GIF 54 kb)

High resolution image (TIF 179 kb)

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Halberstadt, A.L., Slepak, N., Hyun, J. et al. The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents. Psychopharmacology 233, 1215–1225 (2016). https://doi.org/10.1007/s00213-016-4203-3

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