Evaluation of N-acetylcysteine on ethanol self-administration in ethanol-dependent rats.

Many components of ethanol addiction such as reinforcement, withdrawal, extinction, and relapse are known to involve glutamate transmission. NAC could counteract glutamatergic dysregulation underlying ethanol addiction. We previously demonstrated the efficacy of N-acetylcysteine (NAC) treatment to reduce ethanol consumption, motivation, seeking, and relapse in rats displaying a binge drinking-like phenotype. The current study assessed whether acute NAC could reduce ethanol self-administration, ethanol-seeking behavior, motivation, and reacquisition of ethanol self-administration following abstinence in ethanol-dependent rats. Ethanol dependence was induced by chronic intermittent ethanol (CIE) vapor exposure for 10 weeks in male Wistar rats. Effects of NAC (0, 25, 50 or 100 mg/kg; i.p.) were evaluated during acute withdrawal, 8 h after inhalation chambers were turned off. We evaluated NAC effect on the expression of the xCT protein expression (the target of NAC) and glutamate transporters (GLT-1) in dependent rats. We showed that in dependent rats, the low dose of NAC (25 mg/kg) reduced ethanol self-administration and motivation to consume ethanol, evaluated in a progressive ratio paradigm. At 50 mg/kg, but not 25 mg/kg, NAC reduced extinction responding and reacquisition of self-administration after 1 month abstinence. The xCT protein expression was decreased in the nucleus accumbens in dependent compared with ethanol-naïve rats. Thus, NAC may be effective by decreasing glutamate transmission through presynaptic mechanisms (i.e. the stimulation of xc--mediated increase in extrasynaptic glutamate levels). Our results demonstrate that NAC decreased ethanol self-administration, extinction responding, and relapse in ethanol-dependent animals, and thus strongly support clinical development of NAC for alcohol use disorders.

Evaluation of alcohol use disorders pharmacotherapies in a new preclinical model of binge drinking.

Binge drinking is defined as a pattern of drinking leading to intoxication in a single short session and is a serious but preventable public health problem. Only few animal models of voluntary binge drinking using an operant paradigm are available in outbred animals and in general they do not display good face validity. We recently set up a new model of binge drinking behavior using an operant self-administration paradigm in which rats drink to intoxication level in 15-min daily session. Here we tested the current pharmacotherapies of alcohol use disorder: Acamprosate, (R)-Baclofen, gamma-hydroxybutyric acid, Nalmefene and Naltrexone. Our results show that all drugs are effective in reducing ethanol drinking. All drugs except Acamprosate also reduced the motivational properties of ethanol (breakpoint). (R)-Baclofen and gamma-hydroxybutyric acid were effective on ethanol intake at doses devoid of side effects. Among the tested drugs only (R)-Baclofen, gamma-hydroxybutyric acid and Naltrexone reduced reacquisition after a period of abstinence. Interestingly, the efficacy of all drugs except Nalmefene to reduce ethanol drinking was slightly and positively correlated with the basal level of drinking thus revealing heavy drinking as a predictive factor. In summary, all current alcohol use disorder pharmacotherapies were effective in our model of binge drinking behavior thus bringing new data regarding its good predictive validity. The tested drugs display some specificity regarding their effect on motivation, reacquisition and also in terms of individual factors such as basal drinking level. Our new model opens promising perspectives about the development of pharmacotherapies targeting binge drinking behavior.

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

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.

Gasping generation in developing Swiss-Webster mice in vitro and in vivo.

During hypoxia the respiratory network produces gasping in vivo and in vitro. To understand the mechanisms involved in such response and to validate in vitro findings, correlative studies are necessary. During perinatal age gasping generation is robust and then declines during postnatal development, possibly due to changes in either the rhythm generator (the pre-Bötzinger complex, PBC) and/or its motor outputs. We tested this hypothesis by recording respiratory response to hypoxia in vivo and in vitro during postnatal development. We found that postnatal age influences: (1) The hypoxia-induced pattern change in the PBC bursts, (2) The coupling between the PBC and the XII nucleus during prolonged hypoxia and (3) The ability of mice to gasp and autoresuscitate from hypoxic conditions. We conclude that the inability of mice to gasp during late postnatal development might be determined by a progressive uncoupling between the respiratory rhythm generator and its motor outputs in hypoxia.