Commonality of Ethanol and Nicotine Reinforcement and Relapse in Wistar‐Derived UChB Rats: Inhibition by <i>N</i>‐Acetylcysteine

Quintanilla, Marı́a Elena; Morales, Paola; Ezquer, Fernando; Ezquer, Marcelo; Herrera‐Marschitz, Mario; Israel, Yedy

doi:10.1111/acer.13842

Cited by 29 publications

(36 citation statements)

References 74 publications

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“…In rats, ethanol self-administration increased extracellular glutamate levels in the NAcc and VTA [153]. Systemic NAC administration after a period of abstinence from ethanol or nicotine self-administration significantly reduced their respective substance reinstatement, compared to rats administered with saline [65]. In rodent models, the relevance of synaptic (GLT-1) glutamate transport on ethanol and nicotine self-administration was additionally demonstrated by the intranasal administration of the antioxidant and anti-inflammatory secretome derived from mesenchymal stem cells (MSCs), which significantly inhibited the consumption of both drugs, an effect that was fully prevented by brain GLT-1 knockdown [66].…”

Section: The Recovery Of Glt-1 and System XC − Activities Inhibits Drmentioning

confidence: 90%

“…Thus, NAC treatment successfully normalizes the rat brain levels of oxidative stress and inflammation raised by exposure to drugs of abuse like ethanol, nicotine [65,164], and methamphetamine [165], which correlated with a reduction of oral intake of ethanol and nicotine after months of ad libitum consumption in NAC-treated rats [65,166]. The reduction of ethanol and nicotine intake is more pronounced if orally administered NAC is given repeatedly during drug intake [65,166] or intraperitoneally as a bolus at the end of a period of abstinence [167]. As expected, the reduction of rat ethanol consumption was enhanced if NAC was given as a co-treatment with the anti-inflammatory drug aspirin [166], which also reduces the levels of inflammatory factors in the brain (see below).…”

Section: N-acetylcysteine (Nac)mentioning

confidence: 97%

“…NAC antioxidant activity is explained by its direct reducing action of disulfide bonds and by being a precursor of the potent antioxidant glutathione [163]. Thus, NAC treatment successfully normalizes the rat brain levels of oxidative stress and inflammation raised by exposure to drugs of abuse like ethanol, nicotine [65,164], and methamphetamine [165], which correlated with a reduction of oral intake of ethanol and nicotine after months of ad libitum consumption in NAC-treated rats [65,166]. The reduction of ethanol and nicotine intake is more pronounced if orally administered NAC is given repeatedly during drug intake [65,166] or intraperitoneally as a bolus at the end of a period of abstinence [167].…”

Section: N-acetylcysteine (Nac)mentioning

confidence: 99%

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Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

et al. 2020

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Drug abuse is a major global health and economic problem. However, there are no pharmacological treatments to effectively reduce the compulsive use of most drugs of abuse. Despite exerting different mechanisms of action, all drugs of abuse promote the activation of the brain reward system, with lasting neurobiological consequences that potentiate subsequent consumption. Recent evidence shows that the brain displays marked oxidative stress and neuroinflammation following chronic drug consumption. Brain oxidative stress and neuroinflammation disrupt glutamate homeostasis by impairing synaptic and extra-synaptic glutamate transport, reducing GLT-1, and system Xc− activities respectively, which increases glutamatergic neurotransmission. This effect consolidates the relapse-promoting effect of drug-related cues, thus sustaining drug craving and subsequent drug consumption. Recently, promising results as experimental treatments to reduce drug consumption and relapse have been shown by (i) antioxidant and anti-inflammatory synthetic molecules whose effects reach the brain; (ii) natural biomolecules secreted by mesenchymal stem cells that excel in antioxidant and anti-inflammatory properties, delivered via non-invasive intranasal administration to animal models of drug abuse and (iii) potent anti-inflammatory microRNAs and anti-miRNAs which target the microglia and reduce neuroinflammation and drug craving. In this review, we address the neurobiological consequences of brain oxidative stress and neuroinflammation that follow the chronic consumption of most drugs of abuse, and the current and potential therapeutic effects of antioxidants and anti-inflammatory agents and biomolecules to reduce these drug-induced alterations and to prevent relapse.

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Section: The Recovery Of Glt-1 and System XC − Activities Inhibits Drmentioning

confidence: 90%

Section: N-acetylcysteine (Nac)mentioning

confidence: 97%

Section: N-acetylcysteine (Nac)mentioning

confidence: 99%

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Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

et al. 2020

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“…In this regard, drugs that normalize synaptic glutamate homeostasis and neurotransmission (e.g., N-acetylcysteine (NAC), ceftriaxone, clavulanic acid, topiramate) have been reported to attenuate the priming effects of a variety of self-administered drugs in reinstatement studies in rodents (e.g., Amen et al 2011;Johnson et al 2013;Knackstedt et al 2010;LaRowe et al 2013;Moussawi et al 2011;Schmaal et al 2010;Kim et al 2016). For example, NAC has been shown to inhibit reinstatement of extinguished self-administration responding maintained by cocaine (Baker et al 2003;Frankowska et al 2014;Jastrzębska et al 2016;Kau et al 2008;Kupchik et al 2012;Moran et al 2005;Reissner et al 2015;Reichel et al 2011), methamphetamine (Chamtikov et al 2018, heroin (Hodebourg et al 2018;Zhou and Kalivas 2008), alcohol (Quintanilla et al 2018), and nicotine (Ramirez-Nino et al 2013). Moreover, these findings in rodents appear to be functionally consistent with two clinical reports of decreased cocaine craving in human CUD participants following NAC treatment (LaRowe et al 2007;Mardikian et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates

et al. 2019

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Rationale.-Cocaine use disorder (CUD) is associated with cognitive deficits that have been linked to poor treatment outcomes. An improved understanding of cocaine's deleterious effects on cognition may help optimize pharmacotherapies. Emerging evidence implicates abnormalities in glutamate neurotransmission in CUD and drugs that normalize glutamatergic homeostasis (e.g., Nacetylcysteine [NAC]) may attenuate CUD-related relapse behavior. Objectives.-The present studies examined the impact of chronic cocaine exposure on touchscreen-based models of learning (repeated acquisition) and cognitive flexibility (discrimination reversal) and, also, the ability of NAC to modulate cocaine self-administration and its capacity to reinstate drug-seeking behavior. Methods.-First, stable repeated acquisition and discrimination reversal performance was established. Next, high levels of cocaine-taking behavior (2.13-3.03 mg/kg/session) were maintained for 150 sessions during which repeated acquisition and discrimination reversal performance was probed periodically. Finally, the effects of NAC treatment were examined on cocaine self-administration and, subsequently, extinction and reinstatement. Results.-Cocaine self-administration significantly impaired performance under both cognitive tasks; however, discrimination reversal was disrupted considerably more than acquisition. Performance eventually approximated baseline levels during chronic exposure. NAC treatment did not perturb ongoing self-administration behavior but was associated with significantly quicker extinction of drug-lever responding. Cocaine-primed reinstatement did not significantly differ between groups. Conclusions.-The disruptive effects of cocaine on learning and cognitive flexibility are profound but performance recovered during chronic exposure. Although the effects of NAC on models of drug-taking and drug-seeking behavior in monkeys are less robust than reported in rodents, they nevertheless suggest a role for glutamatergic modulators in CUD treatment programs.

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“…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%

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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Commonality of Ethanol and Nicotine Reinforcement and Relapse in Wistar‐Derived UChB Rats: Inhibition by N‐Acetylcysteine

Cited by 29 publications

References 74 publications

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

Oxidative Stress and Neuroinflammation as a Pivot in Drug Abuse. A Focus on the Therapeutic Potential of Antioxidant and Anti-Inflammatory Agents and Biomolecules

Effects of chronic cocaine self-administration and N-acetylcysteine on learning, cognitive flexibility, and reinstatement in nonhuman primates

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

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