title: Identification of miltirone as active ingredient of Salvia miltiorrhiza responsible for the reducing effect of root extracts on alcohol intake in rats.
abstract: BACKGROUND
  Previous work found that extracts from the roots of Salvia miltiorrhiza, a Chinese medicinal herb, reduced alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to evaluate whether miltirone, one of the possible active constituents of S. miltiorrhiza, might be responsible for the reducing effect of the extracts on alcohol intake.
  
  
  METHODS
  An initial experiment assessed the effect of 100 mg/kg (intragastric, i.g.) of 4 extracts of S. miltiorrhiza, differing in miltirone content (0, 2, 3, and 7%, respectively), on alcohol intake in alcohol-experienced sP rats exposed to the 2-bottle "alcohol (10%, volume in volume) versus water" choice regimen. Subsequently, the effect of pure miltirone (2.5-10 mg/kg, i.g., i.e., a dose range comparable to its content in the effective doses of the active extracts) on acquisition and maintenance of alcohol-drinking behavior was evaluated in alcohol-naive and alcohol-experienced sP rats exposed to the 2-bottle choice regimen. The effect of miltirone (10 mg/kg, i.g.) on blood alcohol levels was assessed after the i.g. and intraperitoneal (i.p.) administration of alcohol. Finally, the effect of miltirone (30-100 mg/kg, i.g.) on the severity of alcohol withdrawal syndrome was evaluated in Wistar rats made physically dependent on alcohol by the repeated administration of intoxicating doses of alcohol.
  
  
  RESULTS
  The reducing effect of 4 different extracts of S. miltiorrhiza on alcohol intake was positively and significantly correlated with their miltirone content. Pure miltirone reduced alcohol intake in alcohol-experienced rats and delayed acquisition of alcohol-drinking behavior in alcohol-naive rats. Similar to S. miltiorrhiza extracts, miltirone markedly reduced blood alcohol levels when alcohol was administered i.g. but not i.p., suggesting that miltirone hampered alcohol absorption from the gastrointestinal system. Finally, miltirone failed to affect the severity of alcohol withdrawal syndrome in alcohol-dependent rats.
  
  
  CONCLUSIONS
  The results of the present study suggest that miltirone is the likely active constituent of S. miltiorrhiza responsible for the reducing effect of its extracts on alcohol intake in different experimental models of excessive alcohol consumption.
authors.affiliation: C.N.R. Institute of Neuroscience, Cagliari, Italy. colomb@unica.it
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Serra
authors.forename: Giovanni
authors.initials: G
authors.lastname: Vacca
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orrù
authors.forename: Paola
authors.initials: P
authors.lastname: Maccioni
authors.forename: Paolo
authors.initials: P
authors.lastname: Morazzoni
authors.forename: Ezio
authors.initials: E
authors.lastname: Bombardelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Riva
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: Mauro A M
authors.initials: MA
authors.lastname: Carai
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood; D007700:Kinetics; D008297:Male; D010616:Phenanthrenes / Q000032:analysis* / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D013375:Substance Withdrawal Syndrome
chemical_list: D010616:Phenanthrenes; D010936:Plant Extracts; D011963:Receptors, GABA-A; C068880:miltirone; D000431:Ethanol