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


OBJECTIVE
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.
Fantegrossi
William E
WE
Department of Pharmacology, Medical School, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109-0632, USA. billfan@umich.edu
Kiessel
Christina Lynn
CL
Leach
P Tarn
PT
Van Martin
C
C
Karabenick
Rachel Lynn
RL
Chen
X
X
Ohizumi
Y
Y
Ullrich
Thomas
T
Rice
Kenner C
KC
Woods
James H
JH
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001060:Aporphines / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D003441:Crowding; D004305:Dose-Response Relationship, Drug; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy / Q000401:mortality; D005464:Fluorobenzenes / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010880:Piperidines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D018490:Serotonin Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013237:Stereoisomerism
D000317:Adrenergic alpha-Antagonists; D001060:Aporphines; D005464:Fluorobenzenes; D010880:Piperidines; D018490:Serotonin Agents; D012702:Serotonin Antagonists; C079049:volinanserin; D018817:N-Methyl-3,4-methylenedioxyamphetamine; C041615:nantenine; D011224:Prazosin