S14-3Effect of N-acetylcysteine on motivation, seeking and relapse to ethanol self-administration in alcohol dependent and non-dependent rats
Résumé
Alcohol addiction 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% 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%) and in a progressive ratio schedule (−81%). NAC also reduced ethanol-seeking behavior (−77%) 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. Finally we tested acute intraperitoneal injection of NAC (0, 25, 50 or 100 mg/kg) in rats exposed to chronic intermittent ethanol vapors for 7 weeks. We found that all the tested doses were effective in reducing operant ethanol self-administration, even the low dose (25 mg/kg), thus showing that the hyperglutamatergic state of the withdrawal period may explain the high efficacy of NAC.
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.