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

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. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

In Vitro and In Vivo Characterization of the Alkaloid Nuciferine.

RATIONALE: The sacred lotus (Nelumbo nucifera) contains many phytochemicals and has a history of human use. To determine which compounds may be responsible for reported psychotropic effects, we used in silico predictions of the identified phytochemicals. Nuciferine, an alkaloid component of Nelumbo nucifera and Nymphaea caerulea, had a predicted molecular profile similar to antipsychotic compounds. Our study characterizes nuciferine using in vitro and in vivo pharmacological assays. METHODS: Nuciferine was first characterized in silico using the similarity ensemble approach, and was followed by further characterization and validation using the Psychoactive Drug Screening Program of the National Institute of Mental Health. Nuciferine was then tested in vivo in the head-twitch response, pre-pulse inhibition, hyperlocomotor activity, and drug discrimination paradigms. RESULTS: Nuciferine shares a receptor profile similar to aripiprazole-like antipsychotic drugs. Nuciferine was an antagonist at 5-HT2A, 5-HT2C, and 5-HT2B, an inverse agonist at 5-HT7, a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter. In rodent models relevant to antipsychotic drug action, nuciferine blocked head-twitch responses and discriminative stimulus effects of a 5-HT2A agonist, substituted for clozapine discriminative stimulus, enhanced amphetamine induced locomotor activity, inhibited phencyclidine (PCP)-induced locomotor activity, and rescued PCP-induced disruption of prepulse inhibition without induction of catalepsy. CONCLUSIONS: The molecular profile of nuciferine was similar but not identical to that shared with several approved antipsychotic drugs suggesting that nuciferine has atypical antipsychotic-like actions.

Predisposing effects of neonatal visceral pain on abuse-related effects of morphine in adult male Sprague Dawley rats.

RATIONALE: Adverse early life experiences are risk factors for drug abuse and addiction. Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but the impact of these changes on abuse-related effects of morphine are unknown. The NVP procedure used models chronic visceral hyperalgesia persisting across development. OBJECTIVES: Intravenous self-administration, drug discrimination, and locomotor activity were used to compare the abuse-related effects of morphine in NVP and control rats. METHODS: Rats self-administered 0.3 mg/kg/inj morphine under an FR1 schedule, and dose-effect functions for morphine were then established. Separate rats were trained to discriminate 3.2 mg/kg morphine from saline under an FR20 schedule, and morphine dose-effect functions were then determined in the absence and presence of 0.1 mg/kg naltrexone. A third group of rats was tested with a range of morphine doses in an assay of locomotor activity, then injected daily with 10 mg/kg morphine to assess locomotor sensitization. RESULTS: NVP rats self-administered more morphine than controls at reinforcing doses. Discriminative stimulus effects of morphine were similar between groups, but in the presence of naltrexone, the ED50 for morphine was more than 12× greater in control rats than in NVP animals. Morphine did not stimulate locomotor activity at any tested dose in NVP rats, although significant effects were observed in controls. Finally, significant locomotor sensitization was observed only in NVP rats. CONCLUSIONS: NVP-induced changes in brain opioid systems have persistent pharmacological consequences into adulthood and may increase sensitivity to abuse-related effects of opioids across development.