Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse.
BACKGROUND
Drug challenges in "intact" and p-chlorophenylalanine (p-CPA)-treated animals can be used to distinguish agents that act as direct serotonin (5-HT) agonists from agents that function as 5-HT releasers.


OBJECTIVE
The objective of the study was to investigate the effect of p-CPA treatment on the capacity of racemic 3,4-methylenedioxymethamphetamine (MDMA) and its stereoisomers to induce the head twitch response, hyperthermia, and locomotor stimulation in mice.


METHODS
Pretreatments with either 100 mg/kg p-CPA or equivolume saline were administered for three consecutive days. The following day, mice were either euthanized (to quantify 5-HT tone), tested with various doses of racemic MDMA or one of its enantiomers in the head twitch assay, or challenged with 32 mg/kg racemic MDMA or one of its enantiomers, while temperature and locomotor activity were monitored via radiotelemetry.


RESULTS
p-CPA reduced cortical 5-HT turnover by >70% without altering dopamine turnover. Racemic MDMA did not induce a significant head twitch response in intact or p-CPA-treated mice. S(+)-MDMA and R(-)-MDMA elicited similar head twitch curves in intact mice; p-CPA treatment attenuated this response when induced by S(+)-MDMA but not when elicited by R(-)-MDMA. Neither the hyperthermic nor locomotor-stimulant effects of racemic MDMA were altered by p-CPA treatment. The hyperthermic effects, but not the locomotor-stimulant effects, of S(+)-MDMA were attenuated in mice treated with p-CPA. R(-)-MDMA did not alter core temperature or induce significant locomotor stimulation in intact or p-CPA-treated mice.


CONCLUSIONS
The effects of S(+)-MDMA on core temperature and head twitch behavior are consistent with a mechanism involving 5-HT release, whereas the effects of R(-)-MDMA on head twitch behavior are consistent with a direct agonist mechanism of action. The actions of the racemate on core temperature and locomotor activity likely involve a combination of 5-HT release and direct agonism at 5-HT receptors.
Division of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Drive, Atlanta, GA 30322, USA. wfanteg@emory.edu
William E
WE
Fantegrossi
Christina L
CL
Kiessel
Richard
R
De la Garza
James H
JH
Woods
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D010134:Fenclonine / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D011292:Premedication; D019998:Racemases and Epimerases; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013237:Stereoisomerism
D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D019998:Racemases and Epimerases; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D010134:Fenclonine; D004298:Dopamine