Effect of N‐acetylcysteine on motivation, seeking and relapse to ethanol self‐administration

• Published in: Addiction biology Vol. 23; no. 2; pp. 643 - 652
• Main Authors: Lebourgeois, Sophie, González‐Marín, María Carmen, Jeanblanc, Jerome, Naassila, Mickael, Vilpoux, Catherine
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-03-2018; Wiley
• Subjects: Acetylcysteine; Alcohol; Body weight; Drug self-administration; Ethanol; ethanol self‐administration; Glutamatergic transmission; Life Sciences; Motivation; N‐acetylcysteine; Operant conditioning; rat; relapse; Rodents; seeking; rat; relapse; seeking; ethanol self-administration; N-acetylcysteine
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/adb.12521

Alcohol use disorder is a chronic and highly relapsing disorder, characterized by a loss of control over alcohol consumption and craving. Several studies suggest a key role of glutamate in this disorder. In recent years, the modulation of cystine/glutamate exchange via the xc− system has emerged as a new therapeutic alternative for reducing the excitatory glutamatergic transmission observed after ethanol self‐administration in both rats and humans. The objective of this study was to determine whether a treatment with N‐acetylcysteine (NAC), a cystine prodrug, could reduce ethanol self‐administration, ethanol‐seeking behavior and reacquisition of ethanol self‐administration. Male Long Evans rats were trained to self‐administer 20 percent ethanol in operant cages for several weeks. Once the consumption surpassed 1 g of ethanol/kg body weight/15 minutes, the effect of an acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) 1 hour before the beginning of each test was evaluated on different aspects of the operant self‐administration behavior. We demonstrated antimotivational properties of NAC (100 mg/kg), as ethanol‐reinforced responding was reduced in a fixed ratio (−35 percent) and in a progressive ratio schedule (−81 percent). NAC also reduced ethanol‐seeking behavior (−77 percent) evaluated as extinction responding in a single extinction session. NAC was able to reduce reacquisition in rats that were abstinent for 17 days, while NAC had no effect on ethanol relapse in rats previously exposed to six extinction sessions. Overall, our results demonstrate that NAC limits motivation, seeking behavior and reacquisition in rats, making it a potential new treatment for the maintenance of abstinence.
We report here N‐acetylcysteine (NAC) efficacy to reduce operant ethanol self‐administration in rats during short‐time session of 15 minutes. NAC also reduces seeking and reacquisition following protracted abstinence. Our results suggest for the first time that NAC is a potential new anticraving treatment for reduction of alcohol relapse.