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

• Published in: Psychopharmacology Vol. 233; no. 7; pp. 1215 - 1225
• Main Authors: Halberstadt, Adam L., Slepak, Natalia, Hyun, James, Buell, Mahalah R., Powell, Susan B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-04-2016; Springer; Springer Nature B.V
• Subjects: Acoustic Stimulation; Animal behavior; Animals; Biomedical and Life Sciences; Biomedicine; Complications and side effects; Cyclohexanones - pharmacology; Cyclohexylamines - pharmacology; Drug abuse; Exploratory Behavior - drug effects; Ketamine; Male; Motor Activity - drug effects; Neurosciences; Original Investigation; Pharmacology/Toxicology; Prepulse Inhibition - drug effects; Psychiatry; Rats; Rats, Sprague-Dawley; Reflex, Startle - drug effects; Rodents; Substance-Related Disorders; Methoxetamine; Phencyclidine; (+)-ketamine; Ketamine isomers; Behavioral pattern monitor; Locomotor activity; Prepulse inhibition; S-(+)-ketamine
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4203-3

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.