Abstract
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.
Highlights
The proposal put forward by Quertemont et al (2005) that acetaldehyde generated in the metabolism of ethanol by brain catalase would play a role in eliciting the reinforcing effects of ethanol has been supported by a number of studies
We investigated whether a reduction of ethanol intake induced by NAC follows the activation of the hippocampal nuclear factor erythroid 2related factor 2 (Nrf2)-antioxidant response element (ARE) antioxidant signaling pathway, which could be prevented by inhibition of the xCT cystine-glutamate transporter and by inhibition of the glutamate presynaptic metabotropic mGlu2/3 receptor
Ethanol intake of animals receiving both NAC and acetylsalicylic acid (ASA) (NAC + ASA; 5.5 ± 0.1 g/kg per day; mean ± SEM, n = 6) was decreased by 66% vs. that shown by vehicle-treated animals (P < 0.001) and lower than that shown by rats receiving either NAC or ASA alone (P < 0.001)
Summary
The proposal put forward by Quertemont et al (2005) that acetaldehyde generated in the metabolism of ethanol by brain catalase would play a role in eliciting the reinforcing effects of ethanol has been supported by a number of studies. The logical extension that inhibiting the molecular mechanisms that initiate ethanol intake would inhibit chronic alcohol intake proved to be wrong; several studies showed that ethanol intake by rats that had learned to chronically self-administer ethanol was not inhibited by either: (a) anticatalase inhibitors (Peana et al, 2015); (b) acetaldehyde trapping agents (Peana et al, 2015; Orrico et al, 2017); or (c) anticatalase gene transduction or Aldh gene overexpression (Quintanilla et al, 2012; Karahanian et al, 2015). Treatments with NAC were shown to significantly inhibit both oxidative stress and neuroinflammation (Quintanilla et al, 2018; Israel et al, 2019)
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