Pharmacological characterization of the effects of 3,4-methylenedioxymethamphetamine ("ecstasy") and its enantiomers on lethality, core temperature, and locomotor activity in singly housed and crowded mice.
BACKGROUND
Few studies have directly compared the effects of methylenedioxymethamphetamine (MDMA, "ecstasy") and its enantiomers across measures.


OBJECTIVE
To investigate the capacity of MDMA and its stereoisomers to produce aggregate toxicity in mice, the influence of 5-HT(2) receptors, 5-HT transporters, and ambient temperature on this effect, and to directly compare the racemate and its enantiomers in terms of their effects on core temperature and locomotor activity with and without various serotonergic pretreatments.


METHODS
Mice were injected with various doses of MDMA and its stereoisomers in various housing conditions, with and without pretreatments of serotonergic drugs, and at two distinct ambient temperatures; lethality was quantified 2 h after MDMA administration. For temperature/activity studies, mice were injected with various doses of MDMA and its enantiomers, with and without ketanserin, MDL100907, or fluoxetine pretreatments, and core temperature and locomotor activity data were collected for 24 h.


RESULTS
Racemic MDMA and its isomers produced aggregate toxicity in mice. The lethal effects of racemic MDMA and its enantiomers were differentially attenuated by the various serotonergic pretreatments and manipulation of the ambient temperature across housing conditions. Racemic and S(+)-MDMA produced hyperthermic effects in mice, while R(-)-MDMA did not. The pretreatment drugs attenuated the hyperthermic effects of racemic MDMA, but were less effective in blocking S(+)-MDMA-induced hyperthermia. Racemic MDMA and both enantiomers stimulated locomotor activity, although R(-)-MDMA was least effective. The pretreatments all reduced the locomotor stimulant effects of racemic MDMA but potentiated S(+)-MDMA-induced hyperlocomotion.


CONCLUSIONS
The MDMA isomers have heterogeneous effects that can be demonstrated across a wide range of endpoints.
Fantegrossi
William E
WE
Department of Pharmacology, University of Michigan, Medical School, 1301 MSRB III, Ann Arbor, MI 48109-0632, USA. billfan@umich.edu
Godlewski
Tomek
T
Karabenick
Rachel L
RL
Stephens
Jermaine M
JM
Ullrich
Thomas
T
Rice
Kenner C
KC
Woods
James H
JH
D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D003080:Cold Temperature; D003441:Crowding / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D006213:Hallucinogens / Q000494:pharmacology* / Q000633:toxicity; D007650:Ketanserin / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010880:Piperidines / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012934:Social Isolation / Q000523:psychology*; D013237:Stereoisomerism; D013686:Telemetry
D005464:Fluorobenzenes; D005473:Fluoxetine; D006213:Hallucinogens; D007650:Ketanserin; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C079049:volinanserin