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

Abstract

Methoxetamine (MXE) is a ketamine analogue 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 of acoustic startle (PPI). 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). 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. 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.

Effects of the psychotomimetic benzomorphan N -allylnormetazocine (SKF 10,047) on prepulse inhibition of startle in mice

“…Similar to our findings in rats (Halberstadt et al, 2016), (±)-NANM significantly reduced PPI in mice ( F (3,53) = 14.58, p <0.0001; Fig. 1A).…”

“…It is well established that noncompetitive and competitive NMDA-R antagonists can disrupt PPI in mice and rats (Mansbach and Geyer, 1989, 1991; Curzon and Decker, 1998; Bakashi et al, 1999; Halberstadt et al, 2016). (±)-NANM is a NMDA-R antagonist in vitro (Wong et al, 1986) and both (+)-NANM and (−)-NANM protect mice from seizures induced by administration of NMDA (Singh et al, 1990).…”

“…Uncompetitive NMDA-R antagonists, including PCP, ketamine, methoxetamine, and dizocilpine (MK-801), are known to disrupt prepulse inhibition of startle (PPI) in rodents (Mansbach and Geyer, 1989, 1991; Halberstadt et al, 2016). We recently demonstrated that racemic NANM is also capable of disrupting PPI in rats (Halberstadt et al, 2016).…”

“…We recently demonstrated that racemic NANM is also capable of disrupting PPI in rats (Halberstadt et al, 2016). PPI refers to the phenomenon where the startle response is attenuated if the startling stimulus is preceded by a weak prestimulus, and is often used as a cross-species measure of sensorimotor gating.…”

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

“…( S )‐ketamine, but not ( R )‐ketamine, caused prepulse inhibition (PPI) deficits in mice . Furthermore, the ED 50 of ( R )‐ketamine (6.33 mg/kg) for PPI deficits in rats was higher than that of ( S )‐ketamine (2.86 mg/kg), indicating that ( R )‐ketamine disrupts PPI with 2.5‐fold lower potency than ( S )‐ketamine. In a conditioned place preference (CPP) test, ( S )‐ketamine increased the CPP score in mice .…”