title: Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice.
abstract: BACKGROUND
  A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents.
  
  
  OBJECTIVE
  The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA).
  
  
  METHODS
  Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.o.) before the fourth test day of repeated DID access to 20 % ethanol. Another group of mice had a history of 4 weeks of IA before ADX71441 (3, 10, 17 mg/kg, p.o.) treatment. The opioid antagonist, naltrexone (0.1, 1, 10 mg/kg, i.p.), was administered to different groups of mice in both protocols as a positive control.
  
  
  RESULTS
  In both DID and IA protocols, ADX71441 showed a selective and potent reduction of ethanol drinking, but not water drinking, while naltrexone had a more modest and transient effect on reducing ethanol drinking. The long-lasting effect of ADX71441 agrees with its plasma pharmacokinetics in showing peak concentrations at 2 h followed by a slow decay lasting well beyond 8 h.
  
  
  CONCLUSIONS
  These findings support previous studies demonstrating that GABAB R PAMs decrease voluntary ethanol intake without altering water intake. ADX71441 may be a worthwhile candidate for developing a treatment of alcoholism, yet its site of action in the brain and long-term pharmacological effects require further exploration.
authors: Department of Psychology, Tufts University, 530 Boston Avenue, Medford, MA, 02155, USA.
authors: Lara S
authors: LS
authors: Hwa
authors: Mikhail
authors: M
authors: Kalinichev
authors: Hasnaà
authors: H
authors: Haddouk
authors: Sonia
authors: S
authors: Poli
authors: Klaus A
authors: KA
authors: Miczek
mesh_terms: D000081:Acetamides; D000427:Alcohol Deterrents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000428:Alcohol Drinking / Q000188:drug therapy*; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001426:Bacterial Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D063425:Binge Drinking / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D058786:GABA-B Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000627:therapeutic use; D014157:Transcription Factors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014227:Triazines
chemical_list: C000592313:ADX71441; D000081:Acetamides; D000427:Alcohol Deterrents; D001426:Bacterial Proteins; D058786:GABA-B Receptor Agonists; D014157:Transcription Factors; D014227:Triazines; D009271:Naltrexone
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