title: Comparison of the effect of the GABAΒ receptor agonist, baclofen, and the positive allosteric modulator of the GABAB receptor, GS39783, on alcohol self-administration in 3 different lines of alcohol-preferring rats.
abstract: BACKGROUND
  Administration of the GABA(B)  receptor agonist, baclofen, and positive allosteric modulator, GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. This study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in 3 lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcohol-preferring (sP), and Alko Alcohol (AA).
  
  
  METHODS
  Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-minute sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets.
  
  
  RESULTS
  The rank of order of the reinforcing and motivational properties of alcohol was P>sP>AA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was P>sP>AA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all 3 rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line.
  
  
  CONCLUSIONS
  These results suggest that: (i) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (ii) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (iii) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol self-administration in P, sP, and AA rats may resemble the differential effectiveness of pharmacotherapies among the different typologies of human alcoholics; and (iv) the GABA(B)  receptor is part of the neural substrate mediating the reinforcing and motivational properties of alcohol.
authors.affiliation: Section of Cagliari, Neuroscience Institute, National Research Council of Italy, Monserrato, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Maccioni
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zaru
authors.forename: Barbara
authors.initials: B
authors.lastname: Loi
authors.forename: Carla
authors.initials: C
authors.lastname: Lobina
authors.forename: Mauro A M
authors.initials: MA
authors.lastname: Carai
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Capra
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Serena
authors.initials: S
authors.lastname: Pasquini
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Petri
authors.initials: P
authors.lastname: Hyytiä
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lumeng
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Colombo
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics*; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D000431:Ethanol / Q000008:administration & dosage*; D018757:GABA Modulators / Q000494:pharmacology / Q000627:therapeutic use; D058786:GABA-B Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012055:Reinforcement Schedule; D012646:Self Administration; D013045:Species Specificity
chemical_list: D003517:Cyclopentanes; D018757:GABA Modulators; D058786:GABA-B Receptor Agonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D011743:Pyrimidines; D000431:Ethanol; D001418:Baclofen