title: Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan.
abstract: BACKGROUND
  3,4-Methylenedioxymethamphetamine (MDMA) causes persistent decreases in brain 5-HT content and 5-HT transporter (SERT) binding, with no detectable changes in SERT protein. Such data suggest that MDMA impairs 5-HT transmission but leaves 5-HT nerve terminals intact. To further test this hypothesis, we carried out two types of experiments in rats exposed to high-dose MDMA. First, we examined the effects of MDMA on SERT binding and function using different in vitro assay conditions. Next, we treated rats with the 5-HT precursor, l-5-hydroxytryptophan (5-HTP), in an attempt to restore MDMA-induced depletions of 5-HT.
  
  
  METHODS
  Rats received three i.p. injections of saline or MDMA (7.5 mg/kg), one injection every 2 h. Rats in one group were decapitated, and brain tissue was assayed for SERT binding and [(3)H]5-HT uptake under conditions of normal (100 or 126 mM) and low (20 mM) NaCl concentration. Rats from another group received saline or 5-hydroxytryptophan/benserazide (5-HTP-B), each drug at 50 mg/kg i.p., and were killed 2 h later.
  
  
  RESULTS
  MDMA reduced SERT binding to 10% of control when assayed in 100 mM NaCl, but this reduction was only 55% of control in 20 mM NaCl. MDMA decreased immunoreactive 5-HT in caudate and hippocampus to about 35% of control. Administration of 5-HTP-B to MDMA-pretreated rats significantly increased the 5-HT signal toward normal levels in caudate (85% of control) and hippocampus (66% of control).
  
  
  CONCLUSIONS
  1) Following high-dose MDMA treatment sufficient to reduce SERT binding by 90%, a significant number of functionally intact 5-HT nerve terminals survive. 2) The degree of MDMA-induced decreases in SERT binding depends on the in vitro assay conditions. 3) 5-HTP-B restores brain 5-HT depleted by MDMA, suggesting that this approach might be clinically useful in abstinent MDMA users.
authors.affiliation: Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, P.O. Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: M H
authors.initials: MH
authors.lastname: Baumann
authors.forename: C M
authors.initials: CM
authors.lastname: Dersch
authors.forename: R B
authors.initials: RB
authors.lastname: Rothman
mesh_terms: D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006213:Hallucinogens / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000172:deficiency*; D018490:Serotonin Agents / Q000494:pharmacology / Q000633:toxicity; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D006213:Hallucinogens; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D006916:5-Hydroxytryptophan; D018817:N-Methyl-3,4-methylenedioxyamphetamine