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-HT2A 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.
KeywordsMDMA Nantenine Toxicity Hyperthermia
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.
- Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK (2001) Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol 60:1181–1188PubMedGoogle Scholar
- Drug Abuse Warning Network (2002) The DAWN report: club drugs, 2001 update, October. Office of Applied Studies, Substance Abuse, and Mental Health Services Administration, Washington, D.C.Google Scholar
- Fantegrossi WE, Ulrich T, Rice KC, Woods JH, Winger G (2002) 3,4-methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) and its stereoisomers as reinforcers in rhesus monkeys: serotonergic involvement. Psychopharmacology 161:356–364Google Scholar
- Handley SL, Singh L (1986) Neurotransmitters and shaking behavior: more than a “gut bath” for the brain. Trends Pharmacol Sci 7:324–328Google Scholar
- Nichols DE (1986) Differences between the mechanism of action of MDMA, MBDB, and the classic hallucinogens. Identification of a new therapeutic class: entactogens. J Psychoact Drugs 18:305–313Google Scholar
- Ortmann R, Biscoff S, Radeke E, Bueche O, Delini-Stula A (1982) Correlation between different measures of antiserotonin activity of drugs. Naunyn Schmiedeberg’s Arch Pharmacol 321:265–270Google Scholar
- Pederson NP, Blessing WW (2001) Cutaneous vasoconstriction contributes to hyperthermia induced by 3,4-methylenedioxymethamphetamine (ecstasy) in conscious rabbits. J. Neurosci 21:8648–8654Google Scholar
- Peroutka SJ, Lebovitz RM, Snyder SH (1981) Two distinct central serotonin receptors with different physiological functions. Science (Wash. DC) 212:827–829Google Scholar
- Ribeiro RA, Rodriguez de Lores Arnaiz G (2001) In vitro dose dependent inverse effect of nantenine on synaptosomal membrane K+-p-NPPase activity. Phytomedicine. 8:107–111Google Scholar