title: Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects.
abstract: BACKGROUND
  While the molecular entity responsible for the rewarding effects of virtually all drugs of abuse is known, that for ethanol remains uncertain. Some lines of evidence suggest that the rewarding effects of alcohol are mediated not by ethanol per se but by acetaldehyde generated by catalase in the brain. However, the lack of specific inhibitors of catalase has not allowed strong conclusions to be drawn about its role on the rewarding properties of ethanol. The present studies determined the effect on voluntary alcohol consumption of two gene vectors, one designed to inhibit catalase synthesis and one designed to synthesize alcohol dehydrogenase (ADH), to respectively inhibit or increase brain acetaldehyde synthesis.
  
  
  METHODS
  The lentiviral vectors, which incorporate the genes they carry into the cell genome, were (i) one encoding a shRNA anticatalase synthesis and (ii) one encoding alcohol dehydrogenase (rADH1). These were stereotaxically microinjected into the brain ventral tegmental area (VTA) of Wistar-derived rats bred for generations for their high alcohol preference (UChB), which were allowed access to an ethanol solution and water.
  
  
  RESULTS
  Microinjection into the VTA of the lentiviral vector encoding the anticatalase shRNA virtually abolished (-94% p < 0.001) the voluntary consumption of alcohol by the rats. Conversely, injection into the VTA of the lentiviral vector coding for ADH greatly stimulated (2 to 3 fold p < 0.001) their voluntary ethanol consumption.
  
  
  CONCLUSIONS
  The study strongly suggests that to generate reward and reinforcement, ethanol must be metabolized into acetaldehyde in the brain. Data suggest novel targets for interventions aimed at reducing chronic alcohol intake.
authors.affiliation: Center of Biomedical Research, Faculty of Medicine, Universidad Diego Portales, Santiago, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Karahanian
authors.forename: María Elena
authors.initials: ME
authors.lastname: Quintanilla
authors.forename: Lutske
authors.initials: L
authors.lastname: Tampier
authors.forename: Mario
authors.initials: M
authors.lastname: Rivera-Meza
authors.forename: Diego
authors.initials: D
authors.lastname: Bustamante
authors.forename: Víctor
authors.initials: V
authors.lastname: Gonzalez-Lira
authors.forename: Paola
authors.initials: P
authors.lastname: Morales
authors.forename: Mario
authors.initials: M
authors.lastname: Herrera-Marschitz
authors.forename: Yedy
authors.initials: Y
authors.lastname: Israel
mesh_terms: D000079:Acetaldehyde / Q000819:agonists / Q000378:metabolism*; D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000428:Alcohol Drinking; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000378:metabolism* / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D005822:Genetic Vectors; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D012054:Reinforcement, Psychology; D012201:Reward
chemical_list: D002492:Central Nervous System Depressants; D011355:Prodrugs; D034741:RNA, Small Interfering; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D002374:Catalase; D000079:Acetaldehyde