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

Lebourgeois, Samuel; González-Marín, María Carmen; Antol, Johann; Naassila, Mickaël; Vilpoux, Catherine

doi:10.1016/j.neuropharm.2019.03.010

Cited by 29 publications

(26 citation statements)

References 74 publications

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“…The effect of NAC on alcohol relapse and neuroinflammation was fully reversed by the xCT inhibitor SZ (8 mg/kg per day). These results support the suggestion (Lebourgeois et al, 2019 ) that NAC might be effective in reducing ethanol intake by activation of the xCT -mediated glutamate transporter. The mGlu2/3 receptor inhibitor LY341495 had only a marginal effect on reversing the GSSG/GSH ratio, indicating that lowering of oxidative stress induced by NAC is not primarily associated with the glutamatergic tone.…”

Section: Discussionsupporting

confidence: 92%

“…For several addictive drugs, relapse self-administration has been reported to be inhibited by the antioxidant drug N-acetylcysteine (NAC; Duailibi et al, 2017;Garcia-Keller et al, 2019). For alcohol, studies by Quintanilla et al (2016aQuintanilla et al ( , 2018, Lebourgeois et al (2018Lebourgeois et al ( , 2019, and Israel et al (2019) showed that the administration of NAC markedly inhibits both chronic alcohol intake and relapse intake. Treatments with NAC were shown to significantly inhibit both oxidative stress and neuroinflammation (Quintanilla et al, 2018;Israel et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection

Quintanilla

Ezquer

Morales

et al. 2020

Front. Behav. Neurosci.

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Chronic ethanol intake results in brain oxidative stress and neuroinflammation, which have been postulated to perpetuate alcohol intake and to induce alcohol relapse. The present study assessed the mechanisms involved in the inhibition of: (i) oxidative stress; (ii) neuroinflammation; and (iii) ethanol intake that follow the administration of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory acetylsalicylic acid (ASA) to animals that had consumed ethanol chronically. At doses used clinically, NAC [40 mg/kg per day orally (p.o.)] and ASA (15 mg/kg per day p.o.) significantly inhibited chronic alcohol intake and relapse intake in alcohol-preferring rats. The coadministration of both drugs reduced ethanol intake by 65% to 70%. N-acetylcysteine administration: (a) induced the Nrf2-ARE system, lowering the hippocampal oxidative stress assessed as the ratio of oxidized glutathione (GSSG)/reduced glutathione (GSH); (b) reduced the neuroinflammation assessed by astrocyte and microglial activation by immunofluorescence; and (c) inhibited chronic and relapse ethanol intake. These effects were blocked by sulfasalazine, an inhibitor of the xCT transporter, which incorporates cystine (precursor of GSH) and extrudes extracellular glutamate, an agonist of the inhibitory mGlu2/3 receptor, which lowers the synaptic glutamatergic tone. The inhibitor of mGlu2/3 receptor (LY341495) blocked the NAC-induced inhibition of both relapse ethanol intake and neuroinflammation without affecting the GSSG/GSH ratio. Unlike N-acetylcysteine, ASA inhibited chronic alcohol intake and relapse via lipoxin A4, a strong anti-inflammatory metabolite of arachidonic acid generated following the ASA acetylation of cyclooxygenases. Accordingly, the lipoxin A4 receptor inhibitor, WRW4, blocked the ASA-induced reduction of ethanol intake. Overall, via different mechanisms, NAC and ASA administered in clinically relevant doses combine their effects inhibiting ethanol intake.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection

Quintanilla

Ezquer

Morales

et al. 2020

Front. Behav. Neurosci.

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“…This randomized, placebo-controlled, within-subjects human laboratory experiment was designed to evaluate n -acetylcysteine as a putative pharmacotherapy for alcohol use disorder. The project expanded on work which showed that n -acetylcysteine treatment reduced a range of alcohol related effects, including positive reinforcing effects in preclinical models ( Israel et al, 2019 ; Lebourgeois et al, 2018 , Lebourgeois et al, 2019 ; Mocelin et al, 2019 ; Morais-Silva et al, 2016 ; Quintanilla et al, 2016 ; Schneider et al, 2015 ), but the negative findings align with those of other trials which have failed to show an effect of n -acetylcysteine on substance use or other psychiatric disorder outcomes (e.g., Tomko et al, 2020 ; Yu et al, 2020 ). The reasons for the discrepancy between those preclinical findings and the results of this study could be due to a number of reasons.…”

Section: Discussionmentioning

confidence: 99%

“…Recent preclinical research has identified other promising compounds that also normalize extracellular glutamate levels by improving xCT and GLT-1 expression and function ( Lebourgeois et al, 2018 , Lebourgeois et al, 2019 ; Morais-Silva et al, 2016 ; Quintanilla et al, 2016 ; Schneider et al, 2015 ; Weiland et al, 2015 ). Chief among these is n -acetylcysteine, which ameliorates negative neuroadaptive changes produced by alcohol, as well as alcohol induced behavioral sensitization, anxiety-like behavior and alcohol withdrawal signs in preclinical models ( Mocelin et al, 2019 ; Morais-Silva et al, 2016 ; Schneider et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Chief among these is n -acetylcysteine, which ameliorates negative neuroadaptive changes produced by alcohol, as well as alcohol induced behavioral sensitization, anxiety-like behavior and alcohol withdrawal signs in preclinical models ( Mocelin et al, 2019 ; Morais-Silva et al, 2016 ; Schneider et al, 2015 ). n-Acetylcysteine also reduces alcohol intake in rodents ( Israel et al, 2019 ; Lebourgeois et al, 2018 , Lebourgeois et al, 2019 ; Quintanilla et al, 2016 ). Unlike ceftriaxone, n -acetylcysteine is federally unscheduled, available over the counter and can be administered orally with a low incidence of side effects.…”

Section: Introductionmentioning

confidence: 99%

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Influence of n-acetylcysteine maintenance on the pharmacodynamic effects of oral ethanol

Stoops

Strickland

Hays

et al. 2020

Pharmacology Biochemistry and Behavior

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Rationale Glutamate systems play an important role in the abuse related effects of alcohol. n-Acetylcysteine, a drug that promotes glutamate homeostasis, attenuates a range of alcohol effects in preclinical models. Objectives This human laboratory study determined the influence of n -acetylcysteine maintenance on alcohol self-administration using a model predictive of treatment effectiveness, along with the subjective, performance and physiological effects of alcohol. We hypothesized that n -acetylcysteine would attenuate alcohol self-administration, as well as positive subjective effects of alcohol. Methods Nine subjects with alcohol use disorder completed this within-subjects study. Subjects were maintained on placebo, 1.2 and 2.4 g n -acetylcysteine in random order on an outpatient basis. After five days of maintenance on the target dose, subjects completed overnight inpatient experimental sessions in which the pharmacodynamic effects of alcohol were determined. Results Alcohol produced prototypic effects (e.g., increased breath alcohol concentration, increased ratings of Feel Drink). n-Acetylcysteine did not alter the effects of alcohol. Conclusions These results indicate that although n -acetylcysteine can safely be combined with alcohol, it does not attenuate the abuse related effects of alcohol and is unlikely to be an effective standalone alcohol use disorder treatment. However, considering study limitations, future work is needed to further understand whether and how n -acetylcysteine might be used as a treatment for alcohol use disorder (e.g., in combination with a behavioral treatment or another pharmacological agent).

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Efficacy of N‐acetylcysteine in the prevention of alcohol relapse‐like drinking: Study in long‐term ethanol‐experienced male rats

Cano-Cebrián

Fernández‐Rodríguez

Hipólito

et al. 2020

J of Neuroscience Research

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Alcohol use disorders are chronic and highly relapsing disorders, thus alcoholic patients have a high rate of recidivism for drug use even after long periods of abstinence. The literature points to the potential usefulness of N-acetylcysteine (NAC) in the management of several substance use disorders probably due to its capacity to restore brain homeostasis of the glutamate system disrupted in addiction. However, there is little evidence in the case of alcohol. The aim of this study was to explore the potential anti-relapse efficacy of NAC using the alcohol deprivation effect (ADE) model in long-term experienced rats. Two experiments were performed in male Wistar rats to: (a) test the efficacy of NAC to prevent relapse and (b) discriminate the best administration schedule (intermittent vs. continuous) for NAC. In the first experiment, animals were implanted with mini-osmotic pumps delivering 0 or 1 mg/ hr NAC during 14 days. In a second experiment, rats received 0, 60, or 100 mg/kg once daily by subcutaneous injection. The efficacy to prevent ADE was evaluated in both experiments. NAC subcutaneously administered, either by continuous infusion or by intermittent injections regimen, is able to block the ADE. The best results were obtained after using 60 mg/kg NAC dose. Our findings support the hypothesis that NAC may represent a valuable therapy in the management of alcohol relapse.

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

Cited by 29 publications

References 74 publications

N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection

N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection

Influence of n-acetylcysteine maintenance on the pharmacodynamic effects of oral ethanol

Efficacy of N‐acetylcysteine in the prevention of alcohol relapse‐like drinking: Study in long‐term ethanol‐experienced male rats

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