title: Mechanisms and environmental factors that underlying the intensification of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy)-induced serotonin syndrome in rats.
abstract: BACKGROUND
  Illicit use of 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) may cause a mild or severe form of the serotonin syndrome. The syndrome intensity is not just influenced by drug doses but also by environmental factors.
  
  
  OBJECTIVE
  Warm environmental temperatures and physical activity are features of raves. The purpose of this study was to assess how these two factors can potentially intensify the syndrome.
  
  
  METHODS
  Rats were administered MDMA at doses of 0.3, 1, or 3 mg/kg and examined in the absence or presence of warm temperature and physical activity. The syndrome intensity was estimated by visual scoring for behavioral syndrome and also instrumentally measuring changes in symptoms of the syndrome.
  
  
  RESULTS
  Our results showed that MDMA at 3 mg/kg, but not 0.3 or 1 mg/kg, caused a mild serotonin syndrome in rats. Each environmental factor alone moderately intensified the syndrome. When the two factors were combined, the intensification became more severe than each factor alone highlighting a synergistic effect. This intensification was blocked by the 5-HT2A receptor antagonist M100907, competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist CGS19755, autonomic ganglionic blocker hexamethonium, and the benzodiazepine-GABAA receptor agonist midazolam but not by the 5-HT1A receptor antagonist WAY100635 or nicotinic receptor antagonist methyllycaconitine.
  
  
  CONCLUSIONS
  Our data suggest that, in the absence of environmental factors, the MDMA-induced syndrome is mainly mediated through the serotonergic transmission (5-hydroxytryptamine (5HT)-dependent mechanism) and therefore is relatively mild. Warm temperature and physical activity facilitate serotonergic and other neural systems such as glutamatergic and autonomic transmissions, resulting in intensification of the syndrome (non-5HT mechanisms).
authors.affiliation: Charles E. Schmidt College of Medicine, Florida Atlantic University, 777 Glades Road, Boca Raton, FL, 33431, USA, rtao@fau.edu.
authors.forename: Rui
authors.initials: R
authors.lastname: Tao
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Shokry
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.forename: H Daniel
authors.initials: HD
authors.lastname: Adams
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ma
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004777:Environment; D006358:Hot Temperature / Q000009:adverse effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000633:toxicity*; D020230:Serotonin Syndrome / Q000139:chemically induced* / Q000378:metabolism
chemical_list: D018490:Serotonin Agents; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine