Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse.
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.[1]References
- Serotonin synthesis inhibition reveals distinct mechanisms of action for MDMA and its enantiomers in the mouse. Fantegrossi, W.E., Kiessel, C.L., De la Garza, R., Woods, J.H. Psychopharmacology (Berl.) (2005) [Pubmed]
Annotations and hyperlinks in this abstract are from individual authors of WikiGenes or automatically generated by the WikiGenes Data Mining Engine. The abstract is from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenesOpen Access LicencePrivacy PolicyTerms of Useapsburg