title: Motivation for alcohol becomes resistant to quinine adulteration after 3 to 4 months of intermittent alcohol self-administration.
abstract: BACKGROUND
  Continued consumption of alcohol despite deleterious consequences is a hallmark of alcoholism and represents a critical challenge to therapeutic intervention. Previous rat studies showed that enduring alcohol self-administration despite pairing alcohol with normally aversive stimuli was only observed after very long-term intake (>8 months). Aversion-resistant alcohol intake has been previously interpreted to indicate pathological or compulsive motivation to consume alcohol. However, given the time required to model compulsive alcohol seeking in previous studies, there is considerable interest in developing more efficient and quantitative rodent models of aversion-resistant alcohol self-administration.
  
  
  METHODS
  Outbred Wistar rats underwent 3 to 4 months or approximately 1.5 months of intermittent, home-cage, two-bottle access (IAA) to 20% alcohol (v/v) or water. Then, after brief operant training, the effect of the bitter-tasting quinine (0.1 g/l) on the motivation to seek alcohol was quantified via progressive ratio (PR). Motivation for quinine-adulterated 2% sucrose under PR was assayed in a separate cohort of 3 to 4 months IAA rats. The effects of quinine on home-cage alcohol consumption in IAA rats and rats with continuous access to alcohol were also examined. Finally, a dose-response for quinine taste preference in IAA and continuous-access animals was determined.
  
  
  RESULTS
  Motivation for alcohol after 3 to 4 months IAA, measured using an operant PR procedure, was not altered by adulteration of alcohol with 0.1 g/l quinine. In contrast, after 3 to 4 months of IAA, motivation for sucrose under PR was significantly reduced by adulteration of sucrose with 0.1 g/l quinine. In addition, motivation for alcohol after only approximately 1.5 months IAA was significantly reduced by adulteration of alcohol with 0.1 g/l quinine. Furthermore, home-cage alcohol intake by IAA rats was insensitive to quinine at concentrations (0.01, 0.03 g/l) that significantly reduced alcohol drinking in animals with continuous access to alcohol. Finally, no changes in quinine taste preference after 3 to 4 months IAA or continuous access to alcohol were observed.
  
  
  CONCLUSIONS
  We have developed a novel and technically simple hybrid operant/IAA model in which quinine-resistant motivation for alcohol is evident after an experimentally tractable period of time (3 to 4 months vs. 8 months). Quinine dramatically reduced sucrose and water intake by IAA rats, indicating that continued responding for alcohol in IAA rats despite adulteration with the normally aversive quinine might reflect maladaptive or compulsive motivation for alcohol. This model could facilitate identification of novel therapeutic interventions for pathological alcohol seeking in humans.
authors.affiliation: Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California, USA. woody@gallo.ucsf.edu
authors.forename: Frederic Woodward
authors.initials: FW
authors.lastname: Hopf
authors.forename: Shao-Ju
authors.initials: SJ
authors.lastname: Chang
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Sparta
authors.forename: Michael S
authors.initials: MS
authors.lastname: Bowers
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
mesh_terms: D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009042:Motivation / Q000187:drug effects*; D011803:Quinine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage; D013997:Time Factors
chemical_list: D000431:Ethanol; D013395:Sucrose; D011803:Quinine