title: Preclinical characterization of toluene as a non-classical hallucinogen drug in rats: participation of 5-HT, dopamine and glutamate systems.
abstract: BACKGROUND
  Toluene is a misused inhalant with hallucinogenic properties and complex effects. Toluene blocks N-methyl-D-aspartate (NMDA) receptors, releases dopamine (DA), and modifies several neurotransmitter levels; nonetheless, the mechanism by which it produces hallucinations is not well characterized.
  
  
  OBJECTIVE
  This study aims (a) to study toluene's effects on the 5-HT2A-mediated head-twitch response (HTR), dopamine (DA), and serotonin (5-HT) tissue levels in discrete brain regions; (b) to compare the actions of toluene, ketamine, and 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) on HTR; and (c) to study the pharmacological blockade of toluene's and ketamine's effects by selective drugs.
  
  
  METHODS
  Independent groups of rats inhaled toluene (500-12,000 ppm) for 30 min during which the occurrence of serotonergic signs was analyzed. Brains were obtained after exposure to determine DA and 5-HT levels by HPLC.
  
  
  RESULTS
  Toluene concentration-dependently induced HTR. Other serotonin syndrome signs were evident at high concentrations. Toluene (4000 and 8000 ppm), and ketamine (3 and 10 mg/kg), significantly increased 5-HT levels in the frontal cortex (FC) striatum, hippocampus, and brain stem, as well as DA levels in the striatum and FC. Pretreatment with ketanserin (5HT2A/2C receptor antagonist), M100907 (selective 5-HT2A receptor antagonist), D-serine (co-agonist of the NMDA receptor glycine site), and haloperidol (D2 receptor antagonist) significantly decreased toluene's and ketamine's actions. The 5HT1A receptor antagonist WAY100635 had no effect.
  
  
  CONCLUSIONS
  Toluene stimulates 5HT2A and 5HT2C receptors, and increases 5-HT and DA levels. These actions are similar to those produced by ketamine and involve activation of a complex neurotransmitter network that includes NMDA receptor antagonism.
authors.affiliation: Departamento de Farmacobiología, Cinvestav, México, DF, Mexico.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Rivera-García
authors.forename: Carolina
authors.initials: C
authors.lastname: López-Rubalcava
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Cruz
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018698:Glutamic Acid / Q000378:metabolism*; D006213:Hallucinogens / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage; D014050:Toluene / Q000008:administration & dosage*
chemical_list: D006213:Hallucinogens; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D012701:Serotonin; D014050:Toluene; D018698:Glutamic Acid; D004298:Dopamine