title: Operant, oral alcoholic beer self-administration by C57BL/6J mice: effect of BHF177, a positive allosteric modulator of GABA(B) receptors.
abstract: BACKGROUND
  With its high palatability, near-beer has been successfully used in rats as a vehicle to induce ethanol oral self-administration.
  
  
  OBJECTIVE
  The study aimed to develop an operant model of oral alcoholic beer self-administration promoting a stable intake of pharmacologically relevant amounts of ethanol in free-feeding C57BL/6J mice. It also aimed to assess the model's predictive validity by evaluating the influence of baclofen, a GABA(B) agonist, and BHF177, a GABA(B) positive allosteric modulator, on alcoholic beer self-administration.
  
  
  METHODS
  Mice were trained to self-administer, under a fixed ratio three schedule of reinforcement, 10 μl of beer containing increasing ethanol concentrations (0-18% v/v) in daily 30-min sessions. The effects on motor coordination (rotarod), locomotor activity (open field, automated cages) and anxiety-like behavior (elevated plus maze, EPM) were examined. Baclofen (1.25-5 mg/kg, intraperitoneal, i.p.) and BHF177 (3.75-30 mg/kg, i.p.) were used to see the effects on 9% alcoholic beer and near-beer self-administration.
  
  
  RESULTS
  Near-beer stably maintained operant oral self-administration in mice. Adding ethanol to near-beer reduced the number of active lever presses, while the corresponding amount of ethanol self-administration increased (0.8-1.0 g/kg/session). Motor impairment was observed when more than 1.3 g/kg/session of ethanol was self-administered with beer and slight but consistent hyperlocomotion with more than 0.9-1.0 g/kg/session. BHF177 (15 mg/kg) preferentially reduced 9% alcoholic beer self-administration, while the higher dose (30 mg/kg)-like baclofen 5 mg/kg-also reduced near-beer self-administration.
  
  
  CONCLUSIONS
  The operant model of oral alcoholic beer self-administration in C57BL/6J mice should prove useful for studying ethanol-reinforced behaviors and to identify candidate compounds for the pharmacological management of alcohol addiction.
authors.affiliation: Experimental Psychopharmacology, Department of Neuroscience, "Mario Negri" Institute for Pharmacological Research, Via La Masa 19, 20156 Milan, Italy. alessandro.orru@marionegri.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Orrù
authors.forename: Daniele
authors.initials: D
authors.lastname: Fujani
authors.forename: Chiara
authors.initials: C
authors.lastname: Cassina
authors.forename: Mirko
authors.initials: M
authors.lastname: Conti
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Clemente
authors.forename: Luigi
authors.initials: L
authors.lastname: Cervo
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D001515:Beer; D003216:Conditioning, Operant / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D009636:Norbornanes / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012055:Reinforcement Schedule; D045442:Rotarod Performance Test / Q000379:methods; D012646:Self Administration / Q000379:methods
chemical_list: D058786:GABA-B Receptor Agonists; C560183:N-(bicyclo(2.2.1)hept-2-yl)-2-methyl-5-(4-(trifluoromethyl)phenyl)-4-pyrimidinamine; D009636:Norbornanes; D011743:Pyrimidines; D000431:Ethanol; D001418:Baclofen