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

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.