Phencyclidine-like in vivo effects of methoxetamine in mice and rats

Methoxetamine (MXE), a drug structurally similar to phencyclidine (PCP), produces PCP-like internal effects in rats but is less reinforcing and less stimulating. In drug discrimination tests, MXE and related compounds triggered PCP-lever selection in rats trained to recognize PCP, though MXE caused behavioral disruption in some animals. After continuous PCP infusion, withdrawal disrupted food-rewarded behavior, which MXE dose-dependently reversed. In self-administration tests, MXE was a weaker reinforcer than PCP. In mice, MXE, PCP, and PCE all caused dose-dependent drops in body temperature, but only PCP increased movement. These results suggest MXE shares PCP's subjective effects but has lower abuse potential.

Study at a glance

Abstract

Methoxetamine (MXE) is a novel drug of abuse that is structurally similar to phencyclidine (PCP). In the present study, rats were trained to discriminate PCP from saline and substitution tests were performed with arylcyclohexylamines PCP, eticyclidine (PCE), tenocyclidine (TCP), and MXE. PCP and PCE engendered PCP-lever selection in all subjects, whereas MXE and TCP produced PCP-lever selection in animals that did not display behavioral disruption. Last, the substituted tryptamine dipropyltryptamine (DPT) produced moderate PCP-lever selection and elicited behavioral disruption in all subjects at the highest dose tested. Immediately following the final substitution test in the drug discrimination experiment, the same rats and a separate group of experimentally-naïve rats were implanted with osmotic mini-pumps delivering continuous PCP infusions for 11 days. Consistent with PCP withdrawal, disruption of food-maintained operant responding was observed when the pumps were removed, but cumulative MXE administration dose-dependently reversed this effect. A third group of rats self-administered several unit doses of PCP and MXE. Results of the self-administration tests revealed that MXE was a less effective reinforcer than PCP. Lastly, mice were implanted with radiotelemetry probes to simultaneously monitor thermoregulatory and locomotor responses following injections of PCP, PCE, or MXE. All three arylcyclohexylamines elicited dose-dependent hypothermic effects, but only PCP produced increases in locomotor activity. Together, these findings indicate that MXE elicits PCP-like interoceptive effects, but reduced reinforcing and locomotor stimulant effects in vivo.