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

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.

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 α₁ antagonist prazosin and the selective 5-HT_2A antagonist M100907.

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.

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.

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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These studies were supported by USPHS grants DA09161 and DA05923. The authors express their gratitude to the University of Michigan Undergraduate Research Opportunity Program, and for the expert technical assistance provided by the University of Michigan Unit for Laboratory Animal Medicine staff.

1. Department of Pharmacology, Medical School, University of Michigan, 1301 MSRB III, Ann Arbor, MI, 48109–0632, USA

   William E. Fantegrossi, Christina Lynn Kiessel, P. Tarn Leach, C. Van Martin, Rachel Lynn Karabenick & James H. Woods

2. Laboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Building 8, Room B1-21, Bethesda, MD, 20892, USA

   Thomas Ullrich & Kenner C. Rice

3. Department of Pharmaceutical Molecular Biology, Graduate School of Pharmaceutical Sciences, Tohoku University, 980-8578, Aoba, Aramaki, Aoba-ku, Sendai , Japan

   X. Chen & Y. Ohizumi

1. William E. Fantegrossi
2. Christina Lynn Kiessel
3. P. Tarn Leach
4. C. Van Martin
5. Rachel Lynn Karabenick
6. X. Chen
7. Y. Ohizumi
8. Thomas Ullrich
9. Kenner C. Rice
10. James H. Woods

Correspondence to William E. Fantegrossi.

Fantegrossi, W.E., Kiessel, C.L., Leach, P.T. et al. Nantenine: an antagonist of the behavioral and physiological effects of MDMA in mice. Psychopharmacology 173, 270–277 (2004). https://doi.org/10.1007/s00213-003-1741-2

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• Received: 21 November 2003

• Accepted: 24 November 2003

• Published: 22 January 2004

• Issue Date: May 2004

• DOI: https://doi.org/10.1007/s00213-003-1741-2

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