Efficacy of d-penicillamine, a sequestering acetaldehyde agent, in the prevention of alcohol relapse-like drinking in rats

• Published in: Psychopharmacology 2013-08, Vol.228 (4), p.563-575
• Main Authors: Orrico, Alejandro, Hipólito, Lucía, Sánchez-Catalán, María José, Martí-Prats, Lucía, Zornoza, Teodoro, Granero, Luis, Polache, Ana
• Format: Article
• Language: English
• Subjects: Acetaldehyde - metabolism; Alcohol; Alcohol Drinking - prevention & control; Alcohol, Denatured; Alcoholism; Alcoholism - drug therapy; Animals; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Chelating Agents - administration & dosage; Chelating Agents - pharmacokinetics; Chelating Agents - pharmacology; Diseases; Dosage and administration; Dose-Response Relationship, Drug; Drug therapy; Ethanol - administration & dosage; Health aspects; Infusion Pumps, Implantable; Male; Neurosciences; Original Investigation; Osmotic Pressure; Penicillamine; Penicillamine - administration & dosage; Penicillamine - pharmacokinetics; Penicillamine - pharmacology; Pharmacology/Toxicology; Prevention; Psychiatry; Psychopharmacology; Rats; Rats, Wistar; Relapse; Rodents; Secondary Prevention; Time Factors; Tissue Distribution; Ventral Tegmental Area
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-013-3065-1

Rationale 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. Objectives 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. Conclusion 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.