3,4‐methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein

Two weeks after giving rats MDMA (7.5 mg/kg, three doses) or the toxin 5,7-DHT, the study measured serotonin levels and two protein markers in brain regions. MDMA reduced tissue serotonin by about 50% in cortex, hippocampus, and caudate but did not significantly change the amount of serotonin transporter or glial fibrillary acidic protein, a marker of nerve damage. In contrast, 5,7-DHT reduced serotonin by over 90%, lowered serotonin transporter protein by 20–35%, and increased glial fibrillary acidic protein by 30–39%. The authors conclude that this MDMA regimen does not cause degeneration of serotonin nerve terminals and that lasting serotonin depletion can occur without destroying the axons.

Study at a glance

Abstract

Abstract Previous experiments conducted in this laboratory showed that administration of high‐dose D‐fenfluramine (D‐FEN) and p‐chloroamphetamine (PCA) decreased 5‐HT transporter (SERT) binding and tissue 5‐HT by 30–60% in caudate and whole brain tissue 2 days and 2 weeks after drug administration. However, protein expression as determined by Western blot analysis did not change in either tissue or time point, except for a 30% decrease in the caudate 2 days after PCA administration. In the present study, we studied the effect of MDMA and 5,7‐dihydroxytryptamine (5,7‐DHT) on tissue 5‐HT levels and the protein expression level of SERT and glial fibrillary acidic protein (GFAP), a validated neurotoxicity marker. Hypothesis. MDMA administration decreases SERT expression. Methods. Two weeks after MDMA administration (7.5 mg/kg i.p., q 2 h × 3 doses) or 2 weeks after i.c.v. administration of 5,7,‐DHT (150 μg/rat), male Sprague‐Dawley rats were sacrificed and the caudate, cortex, and hippocampal tissue collected. Western blots for SERT and GFAP were generated using published methods. Tissue 5‐HT levels were determined by HPLC coupled to electrochemical detection. Results. MDMA treatment decreased tissue 5‐HT in cortex, hippocampus, and caudate by about 50%. However, MDMA treatment had no significant effect on expression level of SERT and GFAP in any brain region. In contrast, 5,7‐DHT reduced tissue 5‐HT by more than 90%, decreased SERT protein expression by 20–35%, and increased GFAP by 30–39%. Conclusion. These data suggest the MDMA treatment regimen used here does not cause degeneration of 5‐HT nerve terminals. Viewed collectively with our previous results and other published data, these data indicate that MDMA‐induced persistent 5‐HT depletion may occur in the absence of axotomy. Synapse 53:240–248, 2004. Published 2004 Wiley‐Liss, Inc.