Effects of MDMA and related analogs on plasma 5-HT: Relevance to 5-HT transporters in blood and brain

• Published in: European journal of pharmacology 2012-01, Vol.674 (2-3), p.337-344
• Main Authors: Yubero-Lahoz, Samanta, Ayestas, Mario A., Blough, Bruce E., Partilla, John S., Rothman, Richard B., de la Torre, Rafael, Baumann, Michael H.
• Format: Article
• Language: English
• Subjects: 5-HT (serotonin); Animals; Blood; Brain; Brain - drug effects; Brain - metabolism; Drug abuse; illicit drugs; Intravenous administration; intravenous injection; Male; MDMA; Metabolites; Microdialysis; N-Methyl-3,4-methylenedioxyamphetamine - administration & dosage; N-Methyl-3,4-methylenedioxyamphetamine - analogs & derivatives; N-Methyl-3,4-methylenedioxyamphetamine - metabolism; N-Methyl-3,4-methylenedioxyamphetamine - pharmacology; Platelet; Platelets; Protein Transport - drug effects; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin - blood; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins - blood; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin transporter; SERT (serotonin transporter); Synaptosomes; transporters
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2011.10.033

(±)-3,4-Methylenedioxymethamphetamine (MDMA) is an illicit drug that evokes transporter-mediated release of serotonin (5-HT) in the brain. 5-HT transporter (SERT) proteins are also expressed in non-neural tissues (e.g., blood), and evidence suggests that MDMA targets platelet SERT to increase plasma 5-HT. Here we tested two hypotheses related to the effects of MDMA on circulating 5-HT. First, to determine if MDMA metabolites might contribute to actions of the drug in vivo, we used in vitro microdialysis in rat blood specimens to examine the effects of MDMA and its metabolites on plasma 5-HT. Second, to determine whether effects of MDMA on plasma 5-HT might be used as an index of central SERT activity, we carried out in vivo microdialysis in blood and brain after intravenous MDMA administration. The in vitro results show that test drugs evoke dose-related increases in plasma 5-HT ranging from two- to sevenfold above baseline, with MDMA and its metabolite, (±)-3,4-methylenedioxyamphetamine (MDA), producing the largest effects. The ability of MDMA and related analogs to elevate plasma 5-HT is correlated with their potency as SERT substrates in rat brain synaptosomes. The in vivo results reveal that MDMA causes concurrent increases in extracellular 5-HT in blood and brain, but there are substantial individual differences in responsiveness to the drug. Collectively, our findings indicate that MDMA and its metabolites increase plasma 5-HT by a SERT-dependent mechanism, and suggest the possibility that measures of evoked 5-HT release in blood may reflect central SERT activity.