Beyond the "First Hit": Marked Inhibition by N-Acetyl Cysteine of Chronic Ethanol Intake But Not of Early Ethanol Intake. Parallel Effects on Ethanol-Induced Saccharin Motivation

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2016-05, Vol.40 (5), p.1044-1051
• Main Authors: Quintanilla, María Elena, Rivera-Meza, Mario, Berríos-Cárcamo, Pablo, Salinas-Luypaert, Catalina, Herrera-Marschitz, Mario, Israel, Yedy
• Format: Article
• Language: English
• Subjects: Acetylcysteine - therapeutic use; Acquisition; Alcohol Drinking - drug therapy; Animals; Maintenance; Male; Motivation - drug effects; N-Acetyl Cysteine Saccharin; Rats; Saccharin - administration & dosage; Self Administration; Time Factors; Voluntary Ethanol Drinking
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.13031

Background A number of studies have shown that acetaldehyde synthesized in the brain is necessary to induce ethanol (EtOH) reinforcement in naïve animals (acquisition phase). However, after chronic intake is achieved (maintenance phase), EtOH intake becomes independent of acetaldehyde generation or its levels. Glutamate has been reported to be associated with the maintenance of chronic EtOH intake. The levels of brain extracellular glutamate are modulated by 2 glial processes: glutamate reabsorption via an Na+‐glutamate transporter (GLT1) and a cystine–glutamate exchanger. Chronic EtOH intake lowers GLT1 levels and increases extracellular glutamate. The administration of N‐acetyl cysteine (NAC), a precursor of cystine, has been shown to reduce the relapse of several drugs of abuse, while NAC has not been tested on chronic EtOH intake or on EtOH's influence on the motivation for another drug. These were investigated in the present study. Methods (i) Rats bred for their high EtOH intake were allowed access to 10% EtOH and water up to 87 days. NAC was administered (30 and 60 mg/kg daily, intraperitoneally) for 14 consecutive days, either during the acquisition phase or the maintenance phase of EtOH drinking. (ii) In additional experiments, rats were allowed EtOH (10%) and water access for 61 days, after which EtOH was replaced by saccharin (0.3%) to determine both if chronic EtOH consumption influences saccharin intake and whether NAC modifies the post chronic EtOH saccharin intake. Results NAC did not influence the acquisition (“first hit”) of chronic EtOH intake, but greatly inhibited (60 to 70%; p