title: Efficacy of D-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats.
abstract: BACKGROUND
  Nowadays, very few approved anti-relapse treatments for alcoholism exist, and their overall efficacy can be considered moderate. An exciting rationale drug development opportunity for the treatment of chronic alcoholism is the use of acetaldehyde sequestering agents. Although these compounds are able to attenuate or prevent most of the behavioral and neurochemical effects of ethanol, the efficacy of acetaldehyde sequestration, by using agents such as D-penicillamine (DP), in relapse prevention has not been studied yet.
  
  
  OBJECTIVE
  The aim of this study was to analyze the effects of DP treatment on the alcohol deprivation effect (ADE) in long-term ethanol-experienced rats as a model of relapse behavior and measure drug plasma and brain levels during treatment.
  
  
  METHODS
  Rats were subcutaneously implanted with mini-osmotic pumps delivering 0, 0.25, or 1 mg/h of DP during 1 week. The efficacy to prevent ADE was determined. DP plasma and brain levels achieved during its subcutaneous administration were measured. In a second experiment, animals received bilateral infusions of 0 or 1.5 μg/h of DP directly into pVTA, and the appearance of ADE was evaluated.
  
  
  RESULTS
  One milligram per hour, but not 0.25 mg/h, DP infusion prevented ADE and reduced the total ethanol preference in animals. DP plasma concentrations associated with ADE suppression were around 3-4 μg/ml, and brain DP levels in these conditions were about 2-3 % of those found in plasma. Intra-pVTA DP administration also suppressed ADE.
  
  
  CONCLUSIONS
  DP is able to prevent alcohol-relapse-like drinking in rats suggesting that this drug may be a useful new tool in the management of relapse in alcohol-dependent patients.
authors.affiliation: Departament de Farmàcia i Tecnologia Farmacèutica, Universitat de València, Avda Vicente Andrés Estellés s/n, 46100, Burjassot, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Orrico
authors.forename: Lucía
authors.initials: L
authors.lastname: Hipólito
authors.forename: María José
authors.initials: MJ
authors.lastname: Sánchez-Catalán
authors.forename: Lucía
authors.initials: L
authors.lastname: Martí-Prats
authors.forename: Teodoro
authors.initials: T
authors.lastname: Zornoza
authors.forename: Luis
authors.initials: L
authors.lastname: Granero
authors.forename: Ana
authors.initials: A
authors.lastname: Polache
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D000428:Alcohol Drinking / Q000517:prevention & control*; D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002614:Chelating Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D015918:Infusion Pumps, Implantable; D008297:Male; D009997:Osmotic Pressure; D010396:Penicillamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D055502:Secondary Prevention; D013997:Time Factors; D014018:Tissue Distribution; D017557:Ventral Tegmental Area
chemical_list: D002614:Chelating Agents; D000431:Ethanol; D010396:Penicillamine; D000079:Acetaldehyde