Nantenine: an antagonist of the behavioral and physiological effects of MDMA in mice |
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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 |
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Affiliation: | (1) Department of Pharmacology, Medical School, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109–0632, USA;(2) Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Building 8, Room B1-21, Bethesda, MD 20892, USA;(3) Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, 980-8578 Aoba, Aramaki, Aoba-ku, Sendai , Japan |
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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 1 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. |
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Keywords: | MDMA Nantenine Toxicity Hyperthermia |
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