Nantenine: an antagonist of the behavioral and physiological effects of MDMA in mice.

Abstract

RATIONALE:

No selective antagonists for the effects of MDMA have yet been identified. The structurally-similar, naturally-occurring plant alkaloid nantenine (9,10-methylenedioxy-1,2 dimethoxyaporphine) may represent such a compound.

OBJECTIVES:

To investigate the capacity of nantenine to block and/or reverse MDMA-induced hyperthermia, lethality, locomotor stimulation, and head twitches in mice, and to compare these actions with those of the selective alpha1 antagonist prazosin and the selective 5-HT2A antagonist M100907.

METHODS:

Pretreatments of either 10 mg/kg nantenine or 1 mg/kg prazosin were administered 15 min before 32 mg/kg MDMA; core temperature and locomotor stimulation were then monitored via radiotelemetry for at least 3 h. In further hyperthermia studies, 32 mg/kg MDMA was administered first and temperature was allowed to rise for 30 min; 10 mg/kg nantenine, 1 mg/kg prazosin, or 1 mg/kg M100907 was then administered in an attempt to reverse MDMA-induced hyperthermia. In lethality assays, percent lethality was quantified 2 h after MDMA injection in two distinct housing conditions, one or 12 mice per cage, with or without 15 min pretreatments of 10 mg/kg nantenine or 1 mg/kg prazosin. Drug elicited head twitches were quantified for 10 min following administration of either MDMA enantiomer, with and without pretreatments of 1 mg/kg nantenine, 0.1 mg/kg prazosin, or 0.001 mg/kg M100907.

RESULTS:

Nantenine blocked and rapidly reversed MDMA-induced hyperthermia, attenuated lethality in both housing conditions, and reduced MDMA-induced locomotor stimulation and head twitches in mice. Prazosin blocked, but did not reverse, MDMA-induced hyperthermia, attenuated lethality (more effectively in singly-housed animals), and reduced MDMA-induced locomotor stimulation and head twitches. M100907 did not reverse MDMA-induced hyperthermia, but effectively blocked drug-elicited head twitches.

CONCLUSIONS:

Nantenine functions as an effective antagonist against a wide range of MDMA-induced effects in mice. The antagonist actions of this compound at serotonin and adrenergic receptors may be differentially implicated across endpoints.

• Authors: William E Fantegrossi, Christina Lynn Kiessel, P Tarn Leach, C Van Martin, Rachel Lynn Karabenick, X Chen, Y Ohizumi, Thomas Ullrich, Kenner C Rice, James H Woods
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 173 Issue 3-4 Pg. 270-7 (May 2004) ISSN: 0033-3158 [Print] Germany
• PMID: 14740148 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adrenergic alpha-Antagonists
• Aporphines
• Fluorobenzenes
• Piperidines
• Serotonin Agents
• Serotonin Antagonists
• volinanserin
• N-Methyl-3,4-methylenedioxyamphetamine
• nantenine
• Prazosin

Topics

• Adrenergic alpha-Antagonists (pharmacology)
• Animals
• Aporphines (administration & dosage, pharmacology)
• Behavior, Animal (drug effects)
• Crowding
• Dose-Response Relationship, Drug
• Fever (chemically induced, drug therapy, mortality)
• Fluorobenzenes (pharmacology)
• Male
• Mice
• Motor Activity (drug effects)
• N-Methyl-3,4-methylenedioxyamphetamine (administration & dosage, antagonists & inhibitors, chemistry)
• Piperidines (pharmacology)
• Prazosin (pharmacology)
• Serotonin Agents (administration & dosage, chemistry, pharmacology)
• Serotonin Antagonists (pharmacology)
• Stereoisomerism