William E. Fantegrossi1, 2 Contact Information, Christina L. Kiessel2, Richard De La Garza II3 and James H. Woods2
(1) Division of Neuroscience, Yerkes National Primate Research Center, Emory University, 954 Gatewood Drive, Atlanta, GA 30322, USA
(2) Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0632, USA
(3) Department of Psychiatry, Neuropsychiatric Institute, A8-148, University of California Los Angeles, Los Angeles, CA 90024, USA
Received: 27 November 2004 Accepted: 15 March 2005 Published online: 28 June 2005
Abstract
Rationale 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.
Objectives 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.